Compounds of phosphinanes and azaphosphinanes, a process for their preparation and pharmaceutical compositions containing them

ABSTRACT

Medicinal products containing the same which are useful in treating conditions requiring a TAFIa inhibitor.

The present invention relates to new compounds of phosphinanes andazaphosphinanes, to a process for their preparation, and topharmaceutical compositions containing them.

The compounds of the invention are TAFIa (activated thrombin-activatablefibrinolysis inhibitor) inhibitors.

TAFI (also called plasma procarboxypeptidase B, procarboxypeptidase R orprocarboxypeptidase U) is a plasma glycoprotein of 60 kDa produced bythe liver, which circulates in the form of a zymogen. During bloodcoagulation and fibrinolysis, thrombin and plasmin cleave thepro-segment of TAFI in the region of the Arg92-Ala93 bond and convert itinto an active enzyme, TAFIa, the half-life of which is from 8 to 15minutes at 37° C. Cleavage of the pro-segment by thrombin is acceleratedby thrombomodulin, a cofactor which is present in plasma and at thesurface of vascular endothelial cells (Bouma B N and Meijers J C,Thrombin-activatable fibrinolysis inhibitor, 2003, Journal of Thrombosisand Haemostasis, I: 1566-1574). TAFIa regulates fibrinolysis negativelyby cleaving the C-terminal lysine residues of the fibrin fibres whichappear during the partial degradation of fibrin by the first traces ofplasmin. These C-terminal lysine residues on the partially degradedfibrin behave like ligands of the circulating plasma plasminogen and ofthe tissue plasminogen activator (tPA) generated by the endothelialcells during thrombotic ischaemia. They thus permit localisation of theconversion of plasminogen to plasmin by the tPA without interferenceeither with the circulating plasmin inhibitor α2-antiplasmin or with thecirculating tissue plasminogen activator inhibitor (PAI-1). Cleavage ofthe C-terminal lysine sites by TAFIa therefore reduces the rate at whichplasmin is generated. Endogenous fibrinolysis is then inhibited andlysis of arterial and venous fibrinous thromboses as well as therapeuticthrombolysis undertaken in patients in the acute post-thromboticischaemic phase are likewise diminished. TAFIa inhibitors therefore havethe potential to increase endogenous and therapeutic fibrinolysis and tobehave like antithrombotic and profibrinolytic agents without the riskof major haemorrhage, since they do not interfere either with plateletactivation or with coagulation during blood haemostasis.

The property of inhibiting TAFIa therefore makes it possible to envisageusing the compounds of the invention in the treatment and prevention ofthrombotic events in at-risk patients.

Their use will be valuable in the treatment, prevention and secondaryprevention of vascular complications, more especially cardiovascular,pulmonary and cerebrovascular complications, associated withatherothrombotic diseases, with atherosclerosis, with diabetes, withhyperlipidaemia, with hypertension, with chronic venous diseases, withobesity-related metabolic syndrome or with cancer.

The compounds according to the invention are especially useful for thetreatment, prevention and secondary prevention of myocardial infarction,angina pectoris, cerebrovascular accidents, aortic aneurysms, arteritisof the lower limbs, fibrotic diseases, venous thromboses and pulmonaryembolism.

Vascular risk factors and vascular diseases such as hypertension,obesity, diabetes, cardiac diseases, cerebrovascular diseases andhyperlipidaemia, and therefore atherosclerosis, play a role in thegenesis of dementias such as Alzheimer's disease and vascular dementia(Qiu C., De Ronchi D. and Fratiglioni L., The epidemiology of thedementias: an update, 2007, Current Opinion in Psychiatry, 20: 380-385).The compounds of the invention will therefore also be of use for thetreatment and/or prevention of dementias such as Alzheimer's disease andvascular dementia.

TAFIa lowers endogenous fibrinolytic potential. As TAFIa inhibitors, thecompounds of the present invention are therefore of use to accompanyacute treatment by injectable fibrinolytics, such as recombinant tPA(for example alteplase, tenecteplase, reteplase, desmoteplase),recombinant uPA or streptokinase, which are used in emergencies (forexample myocardial infarction, cerebrovascular accident).

The compounds of the present invention reinforce the activity of theseinjectable fibrinolytics and therefore lead to the use thereof withfewer haemorrhagic and neurotoxic risks (reduction of the dose thereofand therefore reduction of the side-effects thereof).

The present invention relates more especially to compounds of formula(I):

wherein:

Ak₁ represents a C₁-C₆-alkyl chain,

X represents —(CH₂)_(m), —CH(R)—, —CH₂—N(R)—, —N(R)—CH₂— or—CH₂—N(R)—CH₂—,

-   -   m represents 0 or an integer from 1 to 4,    -   R represents a hydrogen atom or a group selected from        C₁-C₆-alkyl, -Ak₂-Ar₁, -Ak₂-Ar₁-Ar₂ and -Ak₂-Ar₁—O—Ar₂,        -Ak₂-cycloalkyl or -Ak₂-OH,        -   Ak₂ represents a linear or branched C₁-C₆-alkyl chain,        -   Ar₁ and Ar₂, which may be identical or different, each            represent an aryl or heteroaryl group,

R₁ and R₂ each represent a hydrogen atom when X represents —(CH₂)_(m)—,—CH(R)—, —N(R)—, —CH₂—N(R)— or N(R)—CH₂—,

or together form a bond when X represents —CH₂—N(R)—CH₂—,

R₃ represents NH₂, Cy-NH₂, Cy-Ak₃-NH₂ or piperidin-4-yl,

-   -   Cy represents a group selected from cycloalkyl, aryl and        heteroaryl,    -   Ak₃ represents a C₁-C₃-alkyl chain,

R₄ and R₅, which may be identical or different, each represent ahydrogen atom or a fluorine atom,

their optical isomers and addition salts thereof with a pharmaceuticallyacceptable acid.

Aryl group is understood as meaning phenyl, naphthyl or biphenyloptionally substituted by one or more identical or different groupsselected from halogen, hydroxy, amino, linear or branched (C₁-C₆)-alkyloptionally substituted by one or more halogen atoms, methylsulphonyl,methylthio, carboxy, linear or branched (C₁-C₆)-alkoxy optionallysubstituted by one or more halogen atoms, linear or branched(C₁-C₆)-aminoalkyl, the amino group of the aminoalkyl group beingoptionally substituted by one or two linear or branched (C₁-C₆)-alkylgroups.

Heteroaryl group is understood as meaning a monocyclic aromatic group ora bicyclic aromatic or partially aromatic group having from 5 to 12 ringmembers and containing one, two or three hetero atoms selected fromoxygen, nitrogen and sulphur, it being understood that the heteroarylmay be optionally substituted by one or more identical or differentgroups selected from halogen, hydroxy, amino, oxo, linear or branched(C₁-C₆)-alkyl optionally substituted by one or more halogen atoms,linear or branched (C₁-C₆)-alkoxy optionally substituted by one or morehalogen atoms, linear or branched (C₁-C₆)-aminoalkyl, the amino group ofthe aminoalkyl group being optionally substituted by one or two linearor branched (C₁-C₆)-alkyl groups.

Among the heteroaryl groups there may be mentioned, without implying anylimitation, the groups pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl,pyrazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazinyl, pyridazinyl benzofuryl, benzothienyl, benzimidazolyl,imidazopyridinyl, isoquinolinyl, dihydrobenzofuryl, dihydrobenzoxazolyl,dihydroindolyl, dihydroindazolyl, benzodioxolyl.

Cycloalkyl group is understood as meaning a monocyclic, saturatedhydrocarbon group having from 5 to 7 ring members, it being understoodthat the ring may be optionally substituted by one or more identical ordifferent groups selected from halogen, linear or branched(C₁-C₆)-alkyl. Among the cycloalkyl groups there may be mentioned,without implying any limitation, the groups cyclopentyl, cyclohexyl,cycloheptyl.

Optical isomers are understood as being the diastereoisomers and theenantiomers.

The compounds of formula (I) have at least one asymmetric centre:

When the configuration of a compound of formula (I) having a singleasymmetric centre is not specified, the compound is obtained in the formof a mixture of the two enantiomers. When the configuration of acompound of formula (I) having two asymmetric centres is not specified,the compound is obtained in the form of a mixture of diastereoisomers.

Among the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric, hydrobromic, sulphuric,phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic,glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic,methanesulphonic, benzenesulphonic, p-toluenesulphonic, camphoric acid.

One aspect of the present invention relates to the compounds of formula(I) wherein Ak₁ represents —(CH₂)₄—.

Another aspect of the present invention relates to the compounds offormula (I) wherein X represents —N(R)—.

Another aspect of the present invention relates to the compounds offormula (I) wherein X represents —N(R)—, —CH₂—N(R)—, —N(R)—CH₂— or—CH₂—N(R)—CH₂—, and R represents a group selected from -Ak₂-Ar₁,-Ak₂-Ar₁-Ar₂ and Ak₂-Ar₁—O—Ar₂.

Another aspect of the present invention relates to the compounds offormula (I) wherein X represents —N(R)—, —CH₂—N(R)—, —N(R)—CH₂— or—CH₂—N(R)—CH₂—, R represents a group selected from -Ak₂-Ar₁,-Ak₂-Ar₁-Ar₂ and Ak₂-Ar₁—O—Ar₂, and Ak₂ represents CH₂—.

Another aspect of the present invention relates to the compounds offormula (I) wherein R₁ and R₂ each represent a hydrogen atom.

Another aspect of the present invention relates to the compounds offormula (I) wherein R₃ represents NH₂.

Another aspect of the present invention relates to the compounds offormula (I) wherein R₄ and R₅ each represent a hydrogen atom.

Another aspect of the present invention relates to the compounds offormula (I) wherein R₁, R₂, R₄ and R₅ each represent a hydrogen atom, R₃represents NH₂, X represents —N(R)—, —CH₂—N(R)—, —N(R)—CH₂— or—CH₂—N(R)—CH₂—, and R represents a group selected from -Ak₂-Ar₁,-Ak₂-Ar₁-Ar₂ and Ak₂-Ar₁—O—Ar₂.

Another aspect of the present invention relates to the compounds offormula (Ia), a particular case of the compounds of formula (I):

wherein Ra represents a group selected from —CH₂—Ar₁ and —CH₂—Ar₁-Ar₂,wherein Ar₁ and Ar₂ are as defined for formula (I).

The present invention relates also to a process for the preparation ofthe compounds of formula (I) starting from the compound of formula (II):

wherein X, R₁, R₂, R₄ and R₅ are as defined for formula (I), Yrepresents a linear or branched C₁-C₄-alkoxy group or a dialkylaminogroup in which the alkyl groups are C₁-C₄, linear or branched,

which is reacted with CO(OG)₂, wherein G represents a protecting groupof the acid function, such as alkyl or benzyl, preferably tert-butyl orbenzyl,

in the presence of a base, to yield the compound of formula (III):

wherein X, Y, R₁, R₂ and G are as defined hereinbefore,

which is reacted, in the presence of a base, with the compoundBr-Ak₁-R′₃, wherein Ak₁ is as defined for formula (I), and R′₃represents N(Boc)₂, Cy-N(Boc)₂, Cy-Ak₃-N(Boc)₂ or N-Boc-piperidin-4-yl,

to yield the compound of formula (IV):

wherein X, Y, R₁, R₂, R₃, Ak₁ and R′₃ are as defined hereinbefore,

the amino, carboxy and phosphinic functions of which are deprotected toyield the compound of formula (I) or an addition salt thereof with apharmaceutically acceptable acid.

The compound of formula (IV) has at least two asymmetric centres:

The diastereoisomers of the compound of formula (IV) can be separated bymeans of a chiral column, allowing the optically pure compounds offormula (I) to be obtained by the process described above.

The nomenclature (3aR*, 4S*, 6aS*) used for theoctahydrophospholo[3,4-c]pyrrole compounds indicates a relativeconfiguration. It means that the compound is in the form of a mixture ofthe compounds of absolute configurations (3aR, 4S, 6aS) and (3aS, 4R,6aR).

The present invention relates also to a process for the preparation ofthe compounds of formula (Ia), a particular case of the compounds offormula (I),

starting from the compound of formula (IVa), a particular case of thecompounds of formula (IV):

wherein Y and G are as defined for formula (II), and Ga represents aprotecting group of the amino function, such as Boc,

which is debenzylated to yield the compound of formula (V):

wherein Y, G and Ga are as defined hereinbefore,

which is subjected to a reductive amination reaction with the aldehydeof formula R₆—CHO, wherein R₆ represents —Ar₁ or —Ar₁-Ar₂, wherein Ar₁and Ar₂ are as defined for formula (I), to yield the compound of formula(VI):

wherein Y, G, Ga and Ra are as defined hereinbefore,

the amino, carboxy and phosphinic functions of which are deprotected toyield the compound of formula (Ia) or an addition salt thereof with apharmaceutically acceptable acid.

The compound of formula (IVa) has two asymmetric centres:

The diastereoisomers of the compound of formula (IVa) can easily beseparated by means of a chiral column, allowing the optically purecompounds of formula (Ia) to be obtained by the process described above.

The compounds of the invention are TAFIa inhibitors.

As such, they can be used in the prevention or treatment of thromboticevents in at-risk patients. Their use will be valuable in the treatmentand prevention of vascular complications, more especiallycardiovascular, pulmonary and cerebrovascular complications, associatedwith atherothrombotic diseases, with atherosclerosis, with diabetes,with hyperlipidaemia, with hypertension, with chronic venous diseases,with obesity-related metabolic syndrome or with cancer.

The compounds according to the invention are especially useful for thetreatment, prevention and secondary prevention of myocardial infarction,angina pectoris, cerebrovascular accidents of any origin (especiallyatherothrombotic, cardioembolic or caused by atrial fibrillation),aortic aneurysms or arteritis of the lower limbs, venous thromboses(especially in catheterised cancer patients) and pulmonary embolism.

Vascular risk factors and vascular diseases such as hypertension,obesity, diabetes, cardiac diseases, cerebrovascular diseases andhyperlipidaemia, and therefore atherosclerosis, play a role in thegenesis of dementias such as Alzheimer's disease and vascular dementia(Qiu C., De Ronchi D. and Fratiglioni L., The epidemiology of thedementias: an update, 2007, Current Opinion in Psychiatry, 20: 380-385).The compounds of the invention will therefore also be of use for thetreatment and/or prevention of dementias such as Alzheimer's disease andvascular dementia.

TAFIa lowers endogenous fibrinolytic potential. As TAFIa inhibitors, thecompounds of the present invention are therefore of use to accompanyacute treatment by injectable fibrinolytics, such as recombinant tPA(for example alteplase, tenecteplase, reteplase, desmoteplase),recombinant uPA or streptokinase, which are used in emergencies (forexample myocardial infarction, cerebrovascular accident).

The compounds of the present invention reinforce the activity of theseinjectable fibrinolytics and therefore lead to the use thereof withfewer haemorrhagic and neurotoxic risks (reduction of the dose thereofand therefore reduction of the side-effects thereof).

The present invention relates also to pharmaceutical compositionscomprising a compound of formula (I) in combination with one or moreinert, non-toxic, pharmaceutically acceptable excipients or carriers.

The useful dosage varies according to the age and weight of the patient,the administration route, the nature and severity of the disorder andany associated treatments, and ranges from 0.5 mg to 1000 mg per day inone or more administrations.

Among the pharmaceutical compositions according to the invention theremay be mentioned more especially those that are suitable for oral,parenteral (intravenous, intramuscular or subcutaneous), per- ortrans-cutaneous, nasal, rectal, perlingual, ocular or respiratoryadministration, and especially tablets or dragées, sublingual tablets,gelatin capsules, capsules, suppositories, creams, ointments, dermalgels, injectable or drinkable preparations, aerosols, and eye or nasaldrops.

According to one aspect of the present invention, the pharmaceuticalcomposition is an injectable preparation for intravenous administration.

According to another aspect of the present invention, the pharmaceuticalcomposition is a tablet for oral administration.

In addition to the compound of formula (I), the tablets according to theinvention comprise one or more excipients or carriers, such as diluents,lubricants, binders, disintegrators, absorbents, colourants andsweeteners.

There may be mentioned as examples of excipients or carriers.

-   -   for the diluents: lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose, glycerol,    -   for the lubricants: silica, talc, stearic acid and its magnesium        and calcium salts, polyethylene glycol,    -   for the binders: aluminium and magnesium silicate, starch,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and polyvinylpyrrolidone,    -   for the disintegrators: agar, alginic acid and its sodium salt,        effervescent mixtures.

The percentage of active ingredient of formula (I) in the tablet ispreferably between 5% and 50% by weight.

According to one aspect of the present invention, the compound offormula (I) according to the present invention is administered inassociation with a fibrinolytic, more especially an injectablefibrinolytic, such as recombinant tPA (for example, alteplase,tenecteplase, reteplase or desmoteplase), recombinant uPA orstreptokinase, or with an anticoagulant, such as, for example, warfarin,dabigatran etexilate, rivaroxaban.

The administration in association may be in the form of a simultaneousor successive co-administration of two separate pharmaceuticalcompositions each containing one of the active ingredients (freeassociation), or in the form of the administration of a fixedassociation of the two active ingredients in the same pharmaceuticalcomposition.

According to one aspect of the present invention, the compound offormula (I) is administered in the form of an injectable preparation, infree association with an injectable preparation of alteplase.

According to another aspect of the present invention, the compound offormula (I) is administered in the form of an injectable preparation, infree association with an injectable preparation of tenecteplase.

The examples which follow illustrate the present invention. Thestructures of the compounds described in the examples have beendetermined by the conventional spectrophotometric techniques (infra-red,nuclear magnetic resonance, mass spectrometry).

ABBREVIATIONS

AcOEt: ethyl acetate

AIBN: azobisisobutyronitrile

DCM: dichloromethane

DEA: diethylamine

DIBAlH: diisobutylaluminium hydride

DMAP: dimethylaminopyridine

DMF: dimethylformamide

DMSO or dmso: dimethyl sulphoxide

OD: optical density

EDTA: ethylenediaminetetraacetic acid

eq: molar equivalent

HMPA: hexamethylphosphoramide

HPLC: high performance liquid chromatography

IR: infra-red

LDA: lithium diisopropylamide

LiHMDS: lithium hexamethyldisilazane or lithium bis(trimethylsilyl)amide

MTBE: methyl tert-butyl ether

RP: rotatory power

NMR: nuclear magnetic resonance

TAFIa: activated thrombin-activatable fibrinolysis inhibitor

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

TMS: trimethylsilyl

tPA: tissue plasminogen activator

uPa: urokinase plasminogen activator or urokinase

Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Procedure for Synthesis of the Side Chains—Procedures I, J, K(Intermediates 204 to 212)

Procedure I:

Caesium carbonate (60 g, 184 mmol, 2 eq) is added in portions to asolution of di-tert-butyl iminodicarboxylate (20 g, 92 mmol) in 1 L ofDMF under an argon atmosphere and at ambient temperature. Vigorousstirring is maintained for 1 hour, before 1,4-dibromobutane (99.2 g, 459mmol, 5 eq) is added. After 24 hours at ambient temperature, thereaction mixture is filtered over Celite and concentrated under reducedpressure. The residue obtained is purified by flash chromatography onsilica gel using as eluant a heptane/AcOEt gradient (100% to 90:10).Intermediate 204 (26.1 g, 74.1 mmol) is obtained in the form of ancolourless oil with a yield of 81%.

¹H NMR: (CDCl₃, 400 MHz) δ 3.60 (t, 2H), 3.42 (t, 2H), 1.87 (quint.,2H), 1.73 (quint., 2H), 1.51 (s, 18H).

IR: 1790-1744-1693 cm⁻¹ (C═O), 1125 cm⁻¹ (C—O).

Intermediate 205 is obtained starting from 1,3-dibromopropane inaccordance with procedure I described hereinbefore.

Product isolated in the form of a colourless oil (24.7 g, 73.0 mmol)with a yield of 79%.

¹H NMR: (CDCl₃, 400 MHz) δ3.6 (m, 2H), 3.5 (t, 2H), 2.05 (quint., 2H),1.51 (s, 18H).

IR: 1791-1744-1693 cm⁻¹ (C═O), 1125 cm⁻¹ (C—O).

Intermediate 206 is obtained starting from 1,5-dibromopentane inaccordance with procedure I described hereinbefore.

Product obtained in the form of a colourless oil (27.9 g, 76.2 mmol)with a yield of 83%.

¹H NMR: (CDCl₃, 400 MHz) δ 3.60 (t, 2H), 3.40 (t, 2H), 1.90 (m, 2H),1.60 (m, 2H), 1.45 (m, 2H), 1.50 (s, 18H) ppm.

IR: 1740, 1693 (C═O), 1787 cm⁻¹ (C═O weak).

Intermediate 207 is obtained starting from 1,6-dibromohexane inaccordance with procedure I described hereinbefore.

¹H NMR: (CDCl₃, 400 MHz) δ 3.58 (t, 2H), 3.40 (t, 2H), 1.89 (m, 2H),1.65-1.25 (m, 6H), 1.45 (m, 6H), 1.51 (s, 18H) ppm.

Procedure J

tert-Butyl iminodicarboxylate (2.47 g, 11.37 mmol, 1 eq) is added, inportions, to a 60% NaH suspension (0.682 g, 17 mmol, 1.5 eq) in amixture of THF (25 mL) and DMF (3 mL) under argon and at ambienttemperature. The reaction mixture is stirred at ambient temperature for15 minutes and then warmed at 45° C. for 45 minutes. This suspension isthen added to a solution of 1,3-dibromomethylbenzene (3 g, 11.37 mmol, 1eq) in THF (100 mL). Stirring is continued at ambient temperature for 16hours. The mixture is hydrolysed dropwise with a 10% NH₄Cl solution (100mL). The organic phase is extracted with AcOEt (2×50 mL), washed with asaturated NaCl solution (50 mL) and dried over MgSO₄. The solvent isevaporated off under reduced pressure and the crude product is purifiedby flash chromatography on silica gel using as eluant a heptane/DCMgradient (50:50 to 100%). Intermediate 208 (2.07 g, 5.17 mmol) isobtained in the form of a colourless oil with a yield of 45%.

¹H NMR: (DMSO-d₆, 400 MHz) δ 7.33 (d, 2H), 7.3 (sl, 1H), δ3.15 (t, 1H),4.70/4.68 (2s, 4H), 1.40 (s, 18H).

IR: 1790-1747-1699 cm⁻¹ (C═O), 1224-1143-1110 cm⁻¹ (C—O—C), 854-781-699cm⁻¹ (CH—Ar).

MS: m/z 422 [M+Na].

Intermediate 209 is obtained starting from 1,4-dibromomethylbenzene inaccordance with procedure J described hereinbefore.

A white solid (2.02 g, 5.05 mmol) is obtained with a yield of 44%.

¹H NMR: (DMSO-d₆, 400 MHz) δ 7.40 (d, 2H), 720 (d, 2H), 4.69 (2s, 4H),1.39 (s, 18H).

IR: 1767-1693 cm⁻¹ (C═O).

MS: m/z 343 [M-C₄H₈].

Procedure K

Diisopropylethylamine (59.34 g, 462 mmol, 2 eq) is added dropwise to asolution of 2-amino-5-methylpyridine (25 g, 230 mmol) in DCM (450 mL) at0° C. under an argon atmosphere. A solution of (Boc)₂O (125.5 g, 575mmol, 2.5 eq) is then added dropwise, followed byN,N-dimethylaminopyridine (28.1 g, 230 mmol, 1 eq). The reaction mixtureis stirred for 15 hours at ambient temperature. The aqueous phase isextracted with AcOEt (2×400 mL). The organic phases are combined andwashed with a 10% NH₄Cl solution (400 mL), with a saturated NaClsolution (400 mL), with a 10% NaHCO₃ solution (400 mL) and finally witha saturated NaCl solution (400 mL). The organic phase is dried overMgSO₄ and the solvent is evaporated off under reduced pressure. Theresidue obtained in purified by flash chromatography on silica gel usingas eluant a heptane/AcOEt gradient (90:10 to 75:25). Intermediate 210(32.78 g, 106.3 mmol) is obtained in the form of a colourless oil with ayield of 46%.

¹H NMR: (400 MHz, CDCl3) δ ppm 8.3 (s, 1H), 7.75 (dd, 1H), 7.1 (d, 1H),2.3 (s, 3H), 1.45 (s, 18H)

IR: 1742-1707 cm⁻¹ (C═O).

AIBN (0.164 g, 1 mmol) is added to a solution of intermediate 210 (3.08g, 10 mmol) and N-bromosuccinimide (1.87 g, 10.5 mmol, 1.05 eq) in CCl₄(50 mL). The reaction mixture is heated at reflux for 20 hours. Once atambient temperature, the insoluble components are filtered off and thefiltrate is concentrated under reduced pressure. The residue is purifiedby flash chromatography on silica gel using as eluant a DCM/AcOEtgradient (from 99:1 to 95:5). Intermediate 211 (2.15 g, 5.56 mmol) isobtained in the form of a white solid with a yield of 56%.

¹H NMR: (400 MHz, CDCl3) δ ppm 8.55 (d, 1H), 7.75 (dd, 1H), 7.3 (d, 1H),4.45 (s, 2H), 1.45 (s, 18H)

IR: 1753-1743-1710 cm⁻¹ (C═O).

Intermediate 212 is obtained starting, from 2-amino-4-methylpyridine inaccordance with procedure K described hereinbefore.

¹H NMR: (400 MHz, CDCl3) δ ppm 8.48 (d, 1H), 7.3 (d, 1H), 7.22 (d, 1H),4.4 (s, 2H), 1.45 (s, 18H)

IR: 1788-1755-1724 cm⁻¹ (C═O).

Procedure A—Synthesis of Examples 1 to 19 Step A1

Tetraethyl orthosilicate (25 mL, 112 mmol, 1.0 eq) is added to asolution of hypophosphorous acid (7.42 g, 112 mmol, 1.0 eq) inacetonitrile (160 mL) under argon and at ambient temperature. Thereaction mixture is heated at reflux for 2 hours 30 minutes and thencooled to ambient temperature. Bromoalkene CH₂═CH—(CH₂)_(m+2)—Br (0.5eq), Pd₂dba₃ (0.769 g, 0.84 mmol) and Xantphos (0.356 g, 0.62 mmol) arethen added and the reaction mixture is heated at reflux for 18 hours.The solution is then filtered over filter paper at ambient temperatureand concentrated under reduced pressure. The crude product is purifiedby flash chromatography on a silica column using a heptane/AcOEtgradient as eluant. The compound of step A1 is obtained in the form ofan oil.

Step A2

A solution of 1.06M LiHMDS/THF (220 mL, 1.0 eq) is added dropwise to asolution, degassed with argon for 30 minutes, of the compound of step A1(233 mmol, 1 eq) in THF (870 mL) at −78° C. After the addition, thereaction mixture is stirred at ambient temperature for 2 hours 30minutes. The reaction is then quenched at 0° C. by addition of asaturated aqueous NaCl solution (870 mL). After extraction with ethylacetate (3×800 mL), the organic phases are combined, washed with asaturated NaCl solution and dried over MgSO₄, before being concentratedunder reduced pressure. The crude product is then purified by flashchromatography on a silica column using as eluant a DCM/EtOH mixture95:5. The compound of step A2 is obtained in the form of an oil.

Step A3

LDA (6.4 mL, 12.8 mmol, 1.5 eq) is added to a solution of the compoundof step A2 (8.5 mmol, 1 eq) in THF (20 mL) at −70° C. and under a streamof argon. Stirring is maintained for 20 minutes. A solution of dibenzylcarbonate (2.88 g, 11.9 mmol, 1.4 eq) in THF (11 mL) is then addeddropwise. The mixture is stirred for 45 minutes, and then a secondaddition of LDA (6.4 mL, 12.8 mmol, 1.5 eq) is carried out. The solutionis stirred for 2 hours at −70° C. A 10% NH₄Cl solution (60 mL) is thenadded dropwise, the temperature of the reaction mixture being maintainedat −70° C. AcOEt (20 mL) is then added and the reaction mixture isgradually brought to ambient temperature. The reaction mixture is thenextracted with AcOEt (2×80 mL). The organic phases are combined anddried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude product is purified by flash chromatography on a silica columnusing as eluant a DCM/EtOH gradient. The compound of step A3 is obtainedin the form of an oil.

Step A4

A solution of intermediate 204 to 212 (7.65 mmol, 1.1 eq.) in 8 ml ofDMSO and then, dropwise, a solution of the compound of step A3 (6.96mmol, 1 eq) in 5 mL of DMSO are added in succession to a 60% NaHsuspension (0.448 g, 11.14 mmol) in 5 mL of DMSO at 10° C. and underargon. When the addition is complete, the reaction mixture is brought toambient temperature and stirred for 3 hours. The treatment is carriedout at 0° C. by adding 10% NH₄Cl (100 mL) and then AcOEt (100 mL). Afterdecantation, the aqueous phase is re-extracted with AcOEt (2×80 mL). Theorganic phases are combined, washed with a saturated NaCl solution (2×80mL), dried over MgSO₄, filtered and concentrated under reduced pressure.The crude product is purified by flash chromatography on a silica columnusing as eluant a DCM/EtOH gradient. The compound of step A4, a mixtureof diastereoisomers, is obtained in the form of a colourless oil.

Step A5

Bromotrimethylsilane (0.721 mL, 5.47 mmol, 8 eq) is added dropwise to asolution of the compound of step A4 (0.683 mmol, 1.0 eq) in DCM (30 mL)at 0° C. and under argon. The mixture is stirred for 20 hours at ambienttemperature. Evaporation under reduced pressure is carried out, and thenthe mixture is evaporated to dryness using a vane-type pump for 30minutes. The mixture is taken up in MeOH (30 mL), stirred for 30 minutesand then evaporated under pressure and to dryness using a vane-type pumpfor 30 minutes. The mixture is taken up in MeOH again, stirred andevaporated. This operation is carried out a third time. The compound ofstep A5 is obtained in the form of the hydrobromide salt and is useddirectly in the following hydrogenation reaction.

Step A6—Examples 1 to 19

10% Pd/C (10 mol %) is added to a solution of the compound of step A5 inMeOH (15 mL). The mixture is stirred for 18 hours under an H₂ atmosphereat ambient temperature. The catalyst is filtered off over a Whatmanfrit. The filtrate is evaporated to dryness. 12 eq of TFA are added tothe crude product. The product is purified by flash chromatography on areverse-phase RP18 column using an H₂O/MeCN/TFA gradient as eluant.After lyophilisation, the expected product (Examples 1 to 19). TFA salt,is obtained in the form of a white hygroscopic solid.

Example 1: 2-(3-Aminopropyl)-1-hydroxy-1-oxo-1-phospholane-2-carboxylicAcid, Trifluoroacetate

Example 1 is obtained starting from intermediate 205 in accordance withprocedure A described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 12-11 (sl, 1H), 8.3-7.3 (sl, 3H), 2.8(q, 2H), 2.25 (m, 1H), 1.9 (m, 1H), 1.8-1.4 (m, 8H)

ESI/FIA/HR and MS/MS: ESI+/−: infusion: [M+H]+=222.1

Elemental analysis: C=35.39 (35.83); H=5.44 (5.11); N=4.60 (4.18)

Example 2: 2-(4-Aminobutyl)-1-hydroxy-1-oxo-1-phospholane-2-carboxylicAcid, Trifluoroacetate

Example 2 is obtained starting from intermediate 204 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 12.5 (sl, 1H), 7.75 (sl, 3H), 2.8 (q,2H), 2.21-1.6 (m, 2H), 1.9-1.35 (m, 2H), 1.8-1.5 (m, 6H), 1.6-1.2 (m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=236.1041 (236.1051)

Elemental analysis: C=38.94 (37.83); H=5.81 (5.48); N=4.50 (4.01)

Example 3:2-[(6-Aminopyridin-3-yl)methyl]-1-hydroxy-1-oxo-1-phospholane-2-carboxylicAcid, Trifluoroacetate

Example 3 is obtained starting from intermediate 211 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13 (sl, 2H), 7.9 (sl, 3H), 7.7 (m, 2H),6.85 (d, 1H), 3.2 (m, 1H), 2.7 (m, 1H), 2.05 (m, 1H), 1.85-1.5 (m, 5H)

ESI/FIA/HR and MS/MS: [M+H]+=271:0842 (271.0847)

Elemental analysis: C=41.20 (40.64); H=4.52 (4.20); N=8.06 (7.29)

Example 4: 2-(5-Aminopentyl)-1-hydroxy-1-oxo-1-phospholane-2-carboxylicAcid, Trifluoroacetate

Example 4 is obtained starting from intermediate 206 in accordance withprocedure A described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 12.5 (sl, 1H), 2.78 (m, 2H), 1.8 to 1.4(m, 4H), 7.68 (sl, 3H), 2.22/1.65 (m, 2H), 1.98/1.3 (m, 2H), 1.52 (t,2H), 1.4 to 1 (m, 4H)

ESI/FIA/HR and MS/MS: [M+H]+=250.1209 (250.1208)

Elemental analysis: C=39.69 (39.68); H=5.91 (5.83); N=4.37 (3.86)

Example 5: 2-(3-Aminopropyl)-1-hydroxy-1-oxo-1-phospholane-2-carboxylicAcid, Trifluoroacetate

Example 5 is obtained starting from intermediate 205 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13.0 (sl, 1H), 7.73 (sl, 3H), 237 (m,2H), 1.93-1.66-1.44 (3*(m, 2+10H)

ESI/FIA/HR and MS/MS: [M+H]+=236.1051 (236.1051)

Elemental analysis: C=38.07 (37.83); H=5.85 (5.48); N=4.11 (4.01)

Example 6: 2-(5-Aminopentyl)-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Trifluoroacetate

Example 6 is obtained starting from intermediate 206 in accordance withprocedure A described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.65 (sl, 3H), 2.75 (m, 2H), 1.9 (m,2H), 1.0-1.85 (m, 14H)

ESI/FIA/HR and MS/MS: ESI +/−: infusion: [M+H]+=264.1

Elemental analysis: C=40.84 (41.39); H=5.66 (6.14); N=3.76 (3.71)

Example 7: 2-(4-Aminobutyl)-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Trifluoroacetate

Example 7 is obtained starting from intermediate 204 in accordance withprocedure A described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.68 (sl, 3H), 2.78 (m, 2H), 2.02 to1.16 (m, 14H)

ESI/FIA/HR and MS/MS: ESI +/−: infusion: [M+H]+=250.1

Elemental analysis: C=39.61 (39.68); H=5.71 (5.83); N=3.86 (3.86)

Example 8: 2-(4-Aminobutyl)-1-hydroxy-1-oxo-1-phosphepane-2-carboxylicAcid, Trifluoroacetate

Example 8 is obtained starting from intermediate 204 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13 to 11.5 (sl, 1H), 7.75 (sl, 3H), 2.8(m, 2H), 2.1 to 1.85 (m, 2H), 1.85 to 1.2 (m, 14H)

ESI/FIA/HR and MS/MS: ESI +/−: infusion: [M+H]+=264.1

Example 9:2-[[4-(Aminomethyl)phenyl]methyl]-1-hydroxy-1-oxo-1-phospholane-2-carboxylicAcid, Trifluoroacetate

Example 9 is obtained starting from intermediate 209 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13 to 12 (sl, 1H), 7.39 (d, 2H), 2.1 to1.5 (m, 6H), 7.22 (d, 2H), 8.3 (sl, 3H), 3.98 (m, 2H), 3.39/2.75 (2dd,2H)

ESI/FIA/HR and MS/MS: [M+H]+=284.1048 (284.1051)

Elemental analysis: C=48.29 (48.84); H=5.45 (5.99); N=4.64 (4.38)

Example 10: 2-(5-Aminopentyl)-1-hydroxy-1-oxo-1-phosphepane-2-carboxylicAcid, Trifluoroacetate

Example 10 is obtained starting from intermediate 206 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 12 (sl, 1H), 7.68 (sl, 3H), 2.76 (m,2H), 2.12 to 1.9 (m, 2H), 1.87 to 1.11 (m, 16H)

ESI/FIA/HR and MS/MS: [M+H]+=278.1518 (278.1521)

Elemental analysis: C=41.99 (42.97); H=6.38 (6.44); N=3.53 (3.58)

Example 11:1-Hydroxy-1-oxo-2-(2-piperidin-4-ylethyl)-1-phosphinane-2-carboxylicAcid, Trifluoroacetate

Example 11 is obtained starting front N-Boc-4-bromoethylpiperidine inaccordance with procedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 12 (sl, 1H), 8.49-8.2 (2*(m, 2H), 3.24(dl, 2H), 2.82 (m, 2H), 1.94-1.65-1.45-1.2 (4*(m, 12H), 1.79 (tl, 2H),1.39 (m, 1H), 1.2 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=290.1526 (290.1521)

Elemental analysis: C=44.65 (44.67); H=5.93 (6.25); N=3.41 (3.47)

Example 12:2-[[-(Aminomethyl)phenyl]methyl]-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Trifluoroacetate

Example 12 is obtained starting from intermediate 208 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.19 (sl, 3H), 7.3 (m, 2H), 7.22 (s,1H), 7.14 (d, 1H), 3.99 (m, 2H), 3.32/2.97 (2dd, 2H), 1.9 to 1.4 (m, 8H)

ESI/FIA/HR and MS/MS: [M+H]+=298.12 (298.120821)

Elemental analysis: C=47.00 (46.72); H=4.82 (5.15); N=3.39 (3.41)

Example 13: 2-(6-Aminohexyl)-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Trifluoroacetate

Example 13 is obtained starting from intermediate 207 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.65 (sl, 3H), 2.77 (m, 2H), 1.93 (m,2H), 1.8 to 1.14 (m, 16H)

ESI/FIA/HR and MS/MS: [M+H]+=278.1522 (278.15212)

Elemental analysis: C=42.69 (42.97); H=6.26 (6.44); N=3.79 (3.58)

Example 14: 2-(4-Aminobutyl)-1-hydroxy-1-oxo-1-phosphocane-2-carboxylicAcid, Trifluoroacetate

Example 14 is obtained starting from intermediate 204 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.72 (sl, 3H), 2.8 (m, 2H), 2.11 to1.32 (m, 18H)

ESI/FIA/HR and MS/MS: [M+H]+=278.1522 (278.1521)

Elemental analysis: C=43.34 (42.97); H=6.35 (6.44); N=2.91 (3.58)

Example 15:2-[(2-Aminopyridin-4-yl)methyl]-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Trifluoroacetate

Example 15 is obtained starting from intermediate 212 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13.5 to 12 (sl, 1H), 7.8 (d, 1H), 7.87(sl, 3H), 6.75 (s, 1H), 6.6 (d, 1H), 3.25/3 (m, 2H), 2 to 1.35 (m, 8H)

ESI/FIA/HR and MS/MS: [M+H]+=285.1012 (285.1004)

Example 16:2-[2-(trans-4-Aminocyclohexyl)ethyl]-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Trifluoroacetate

Example 16 is obtained starting from tert-butyl[trans-4-(2-bromoethyl)cyclohexyl]-carbamate, in accordance withprocedure A described hereinbefore.

¹H NMR: (300/400/500 MHz, dmso-d6) δ ppm 7.9 (sl, 3H), 2.9 (m, 1H), 2.01(m, 2H), 1.91-1.74 (2m, 4H), 1.64 (m, 2H), 1.53 (m, 2H), 1.39 (m, 2H),1.29-0.95 (m, 4H), 1.11 (m, 4H), 1.09 (m, 1H)

¹³C NMR: (300/400/500 MHz, dmso-d6) δ ppm 49.8, 36.8, 31.6, 30.8, 30.5,30.5, 30.5, 23.6, 22.9

ESI/FIA/HR and MS/MS: [M+H]+=304.1648 (304.1677)

Example 17:2-[2-(cis-4-Aminocyclohexyl)ethyl]-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Trifluoroacetate

Example 17 is obtained starting from tert-butyl[cis-4-(2-bromoethyl)cyclohexyl]carbamate, in accordance with procedureA described hereinbefore.

¹H NMR: (400/500 MHz, dmso-d6) δ ppm 7.9 (sl, 3H), 3.15 (m, 1H),1.96-1.62 (2m, 2H), 1.94-1.73 (2m, 2H), 1.71-1.65 (2m, 2H), 1.68-1.65(2m, 2H), 1.56-1.39 (m, 4H), 1.49-1.36 (2m, 2H), 1.38 (m, 1H), 1.23-1.16(2m, 2H)

¹³C NMR: (400/500 MHz MHz, dmso-d6) δ ppm 173.3, 51, 4.79, 34, 31, 28.7,27.9, 26.5, 26.5, 23.4, 21.6

¹³C NMR: (400/500 MHz, dmso-d6) δ ppm 173.3, 51, 47.9, 34, 31, 28.7,27.9, 26.5, 26.5, 23.4, 21.6

ESI/FIA/HR and MS/MS: [M+H]+=304.1671 (304.1677)

Elemental analysis: C=45.47 (46.05); H=6.68 (6.52); N=3.58 (3.36)

Example 18: 2-(5-Aminopentyl)-1-hydroxy-1-oxo-1-phosphocane-2-carboxylicAcid, Trifluoroacetate

Example 18 is obtained starting from intermediate 206 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 12.0-11.0 (sl, 1H), 7.7 (m, 3H), 2.8(m, 2H), 2.05 (m, 2H), 1.9-1.3 (m, 18H)

ESI/FIA/HR and MS/MS: [M+H]+=292.1656 (292.1677)

Elemental analysis: C=44.17 (44.45); H=6.69 (6.71); N=3.42 (3.46)

Example 19: 2-(5-Aminopentyl)-1-hydroxy-1-oxo-1-phosphonane-2-carboxylicAcid, Trifluoroacetate

Example 19 is obtained starting from intermediate 206 in accordance withprocedure A described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 12.4-11 (sl, 1H), 7.7 (sl, 3H), 2.75(t, 2H), 2.3 (m, 1H), 2.05 (m, 1H), 1.9-1.2 (m, 20H):

ESI/FIA/HR and MS/MS: [M+H]+=306.1834 (306.1834)

Elemental analysis: C=45.54 (45.82); H=6.98 (6.97); N=3.26 (3.34)

Procedure B—Synthesis of the Phosphinanes Step B1 (Intermediate 6)

Ethyl (triphenylphosphorylidene)acetate (100 g, 287 mmol, 1.2 eq) isadded in portions to a solution of phenylacetaldehyde (28.74 g, 239mmol) in DCM (380 mL) and at ambient temperature. The reaction mixtureis stirred for 20 hours at ambient temperature and then the mixture isconcentrated in vacuo. The residue is taken up in heptane (400 mL),stirred for 1 hour, and then the insoluble component is filtered off.The heptane is evaporated off in vacuo and the residue obtained ispurified by flash chromatography on silica gel using as eluant aheptane/DCM mixture (60:40). Intermediate 6 (27.25 g, 143 mmol) isobtained in the form of a colourless oil with a yield of 60%.

¹H NMR: (400 MHz, CDCl3) δ ppm 7.3 (t, 2H), 7.25 (t, 1H), 7.2 (d, 2H),7.1 (dt, 1H), 5.8 (d, 1H), 4.2 (quad, 2H), 3.5 (d, 2H), 1.3 (t, 3H)

IR (cm⁻¹); 1716, 1653

Step B2 (Intermediate 7)

A solution of 1M DIBAlH in THF (355 mL, 355 mmol) is added to a solutionof intermediate 6 (28.35 g, 149 mmol) in DCM (375 mL) at ambienttemperature and under an argon atmosphere. After 45 minutes at 0° C.,the reaction mixture is stirred for 16 hours at ambient temperature. Thereaction mixture is then cooled to 0° C. and treated with 3N HCl (300mL). The mixture is extracted with DCM (350 mL), and the organic phaseis washed with H₂O (2×100 mL), dried over Na₂SO₄ and then evaporated invacuo. The residue obtained is purified by flash chromatography onsilica gel using as eluant a heptane/AcOEt mixture (75:25). Intermediate7 (16.05 g, 108 mmol) is obtained in the form of a colourless oil with ayield of 72%.

¹H NMR: (400 MHz, CDCl3) δ ppm 7.1-7.4 (m, 5H), 5.65-5.9 (2m, 2H), 4.1(d, 2H), 3.35 (d, 2H), 1.5 (m, 1H)

IR (cm⁻¹): 3600-3200, 1716, 1650

Step B3 (Intermediate 8)

A mixture of intermediate 7 (3.7 g, 25 mmol) with triethyl orthoacetate(16:2 g, 100 mmol, 4 eq) and propionic acid (5 drops) is stirred for 1hour 20 minutes in a microwave (250 W) at 140° C. The mixture is takenup in Et₂O (300 mL) and H₂O (100 mL). The organic phase is then washedwith H₂O (100 mL), dried over MgSO₄ and then concentrated in vacuo. Theresidue obtained is purified by flash chromatography on silica gel usingas eluant a heptane/AcOEt mixture (80:20). Intermediate 8 (4.53 g, 20.7mmol) is obtained in the form of an oil with a yield of 83%.

¹H NMR: (400 MHz, CDCl3) δ ppm 7.15-7.3 (m, 5H), 5.7 (m, 1H), 5 (m, 2H),4.1 (q, 2H), 2.85 (m, 1H), 2.7 (m, 2H), 2.25-2.4 (m, 2H), 1.25 (t, 3H)

IR (cm⁻¹): 1732, 699-747

Step B4 (Intermediate 9)

LiAlH₄ (6.12 g, 161 mmol, 2 eq) is added in portions to a solution ofintermediate 8 (17.58 g, 80:5 mmol) in THF (275 mL) at 0° C. and underargon. The reaction mixture is stirred at ambient temperature for 16hours. Excess LiAlH₄ is hydrolysed by addition of H₂O (4.2 mL) and thenwith a 20% NaOH solution (3.4 mL) and H₂O (15.4 mL). The precipitate isfiltered off and the filtrate is evaporated in vacuo. The residueobtained is purified by flash chromatography on silica gel using aseluant a heptane/AcOEt mixture (70:30). Intermediate 9 (8.09 g, 45.9mmol) is obtained in the form of a colourless oil with a yield of 57%.

Step B5 (Intermediate 10)

Triphenylphosphine (24.07 g, 91.8 mmol, 2 eq) is added in portions to asolution of intermediate 9 (8.09 g, 45.9 mmol) and CBr₄ (30.4 g, 91.8mmol) at ambient temperature in Et₂O (325 mL). The mixture is stirredfor 16 hours. The reaction mixture is filtered and the filtrate isevaporated in vacuo. The residue is taken up in heptane (250 mL),stirred for 30 minutes and then filtered. The filtrate is evaporated invacuo. The residue obtained is purified by flash chromatography onsilica gel using heptane as eluant. Intermediate 10 (8.64 g, 36 mmol) isobtained in the form of a colourless oil with a yield of 78%.

¹H NMR: (400 MHz, CDCl₃) δ ppm 7.28 (t, 2H), 7.18 (t, 1H), 7.13 (d, 2H),5.53 (ddd, 1H), 5.02 (d, 1H), 5 (d, 1H), 3.42 (m, 1H), 3.3 (m, 1H), 2.65(d, 2H), 2.53 (m, 1H), 1.95 (m, 1H), 1.8 (m, 1H)

IR (cm⁻¹): 916, 739-698

Step B6 (Intermediate 11)

Tetraethyl orthosilicate (3.48 g, 16.7 mmol, 1 eq) is added to asolution of hypophosphorous acid (1.1 g, 16.7 mmol) in acetonitrile (25mL) under argon and at ambient temperature. The reaction mixture isheated at reflux for 2 hours 30 minutes and then cooled to ambienttemperature. The reaction mixture is degassed with argon and then thereare added in succession intermediate 10 (2 g, 8.36 mmol) in solution inMeCN (5 mL), Xantphos (0.048 g, 0.0836 mmol) and then Pd₂dba₃ (0.038 g,0.0418 mmol). The mixture is heated at reflux for 16 hours. Afterevaporation in vacuo, the residue obtained is purified by flashchromatography on silica gel using AcOEt as eluant. Intermediate 11(1.61 g, 4.85 mmol) is obtained in the form of an oil with a yield of58%.

¹H NMR: (400 MHz, dmso-d6) δ ppm centred at 6.95 (d, 1H), 7.3 (t, 2H),7.2 (m, 3H), 4 (m, 2H), 3.55 (m, 2H), 2.59 (d, 2H), 1.9 (m, 1H), 1.78(m, 4H), 1.45 (m, 2H), 1.21 (t, 3H)

IR (cm⁻¹): 2343

Step B7 (Intermediate 12)

A solution of 1.06 M LiHMDS in THF (4.53 mL, 4.8 mmol, 1 eq) is addeddropwise at −78° C. to a solution of intermediate 11 (1.6 g, 4.8 mmol)in 50 mL THF and under an argon atmosphere. The reaction mixture isstirred for 30 minutes at −78° C. and then for 4 hours 30 minutes atambient temperature, before being treated with a saturated NaCl solution(50 mL). After addition of AcOEt (150 mL), the organic phase is driedover MgSO₄ and then evaporated in vacuo. The residue obtained ispurified by flash chromatography on silica gel using a DCM/EtOH mixture(95:5) as eluant. Intermediate 12 (0.889 g, 3.52 mmol) is obtained inthe form of a colourless oil with a yield of 73%.

¹H NMR: (400 MHz, CDCl3) δ ppm 7.3 (t, 2H), 7.2 (t, 1H), 7.12 (d, 2H),4.08 (m, 2H), 2.6/2.51 (2d, 2H), 2.1-1.8 (m, 4H), 1.8-1.55 (m, 3H),1.5-1.3 (m+t, 5H)

IR (cm⁻¹): 3433

Step B8 (Intermediate 13)

A solution of 2M LDA in THF (2.6 mL, 5.2 mmol, 1.5 eq) is added to asolution of intermediate 12 (0.875 g, 3.47 mmol) in THF (10 mL) at −78°C. and under argon. After 40 minutes, a solution of dibenzyl carbonate(1.18 g, 4.85 mmol) in THF (5 mL) is added dropwise. The reactionmixture is stirred for 1 hour, and then a further 1.5 eq of 2M LDA inTHF (2.6 mL, 5.2 mmol) is added. After 4 hours at −78° C., the reactionmixture is hydrolysed while cold with a 10% aqueous NH₄Cl solution (9mL). AcOEt (18 mL) and a 10% aqueous NH₄Cl solution (18 mL) are thenadded. After returning to ambient temperature, the reaction mixture isextracted with AcOEt (2×50 mL). The organic phase is dried over MgSO₄and then concentrated in vacuo. The residue obtained is purified byflash chromatography on silica gel using a DCM/EtOH mixture (97.5:2.5)as eluant. Intermediate 13 (0.996 g, 2.58 mmol) is obtained in the formof an oil with a yield of 74%.

¹H NMR: (400 MHz, CDCl3) δ ppm 7.4-7 (m, 10H), 5.18 (s, 2H), 4.15-3.9(m, 2H), 3.2-2.8 (1 dd, 1H), 2.58 (d, 2H), 2.3-1.4 (m, 7H), 1.25 (t, 3H)

IR (cm⁻¹): 1726

Step B9 (Intermediate 14)

A solution of intermediate 206 (1.11 g, 3.03 mmol, 1.3 eq) in DMSO (5mL) and a solution of intermediate 13 (0.9 g, 2.33 mmol) in DMSO (4 mL)are added dropwise, in succession, to a suspension of sodium hydride(0.150 g, 3.75 mmol, 1.6 eq) in DMSO (5 mL). After stirring for 4 hoursat ambient temperature, the reaction mixture is added at 0° C. to amixture (1:1) of a 10% NH₄Cl solution (100 mL) and AcOEt (100 mL). Theaqueous phase is re-extracted with AcOEt (2×50 mL). The organic phasesare combined, dried over MgSO₄ and then concentrated in vacuo.Intermediate 14 so obtained is used directly without being purifiedfurther.

Step B10 (Intermediates 15 and 16)

TMSBr (3.68 mL, 28 mmol, 12 eq) is added to a solution of intermediate14 (1.56 g, 2.33 mmol) in DCM (125 mL) at ambient temperature and underargon. The reaction mixture is stirred for 16 hours at ambienttemperature, before being concentrated in vacuo. The oil obtained istaken up in MeOH (60 mL), stirred for 30 minutes and concentrated invacuo. The same operation is repeated twice. The residue obtained ispurified by reverse-phase chromatography using as eluant an H₂O/MeCN/TFAgradient. Intermediates 15 (0.423 g, 0.95 mmol) and then 16 (0.155 g,0.35 mmol) (in the order of elution) are obtained in the form of whitesolids after lyophilisation with yields of 41% and 15%, respectively.The absolute configuration of intermediates 15 and 16 has not beenverified.

Intermediate 15: Benzyl2-(5-aminopentyl)-4-benzyl-1-hydroxy-1-oxo-1-phosphinane-2-carboxylate,trifluoroacetate-dia 1 racemic

¹H NMR: (400 MHz, dmso-d6) δ ppm 12 (m, 1H), 7.75 (m, 3H), 7.35-7.05 (m,10H), 5.18/5 (2d, 2H), 2.6 (m, 3H), 2.4 (dd, 1H), 2.1 (m, 1H), 1.9-1.5(m, 8H), 1.4 (m, 2H), 1.15 (m, 2H), 0.8/0.52 (2m, 2H)

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −74

IR (cm⁻¹): 3300-2500, 1716, 1678

Intermediate 16: Benzyl2-(5-aminopentyl)-4-benzyl-1-hydroxy-1-oxo-1-phosphinane-2-carboxylate,trifluoroacetate-dia 2 racemic

¹H NMR (400 MHz, dmso-d6) δ ppm 7.4 (m, 5H), 7.25 (t, 2H), 7.18 (t, 1H),7 (d, 2H), centred at 5.11 (AB, 2H), 7.65 (m, 3H), 2.71 (m, 2H), 2.4 (d,2H), 1.95-1.1 (m, 15H)

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −74

IR (cm⁻¹): 3300-2500, 1774, 1716, 1676

Example 20:2-(5-Aminopentyl)-4-benzyl-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Dia 1 Racemic

Intermediate 15 (0.413 g, 0.74 mmol) in solution in 60 mL of a H₂O/MeOHmixture (3:1) is stirred at ambient temperature under an H₂ atmosphere,in the presence of 10% Pd/C (41 mg), for 4 hours. The reaction mixtureis filtered and then concentrated in vacuo. The residue obtained ispurified by reverse-phase chromatography using as eluant an H₂O/MeCNgradient. Example 20 (0.209 g, 0.591 mmol) is obtained in the form of awhite solid after lyophilisation with a yield of 80%.

¹H NMR: (500 MHz, D2O) δ ppm 7.3 (t, 2H), 7.24 (d, 2H), 7.19 (t, 1H),2.59/2.37 (m, 2H), 2.41 (t, 2H), 1.21/1.55 (m, 2H), 1.77/1.6 (m, 2H),1.77/1.35 (m, 2H), 1.64/1.38 (m, 2H), 1.63 (m, 1H), 1.24 (m, 2H),1.16/1.1 (m, 2H), 0.7 (m, 2H)

¹³C NMR: (500 MHz, D2O) δ ppm 129.2, 128.2, 125.7, 42.5, 40, 35.5, 35.4,31.3, 31.1, 30.2, 26, 25.9, 22.8

IR (cm⁻¹): 3300-2100, 1691, 1631, 1605

Elemental analysis: C=60.65 (61.18); H=7.58 (7.99); N=3.91 (3.96)

ESI/FIA/HR and MS/MS: [M+H]+=354.1831 (354.1834)

Example 21:2-(5-Aminopentyl)-4-benzyl-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Dia 2 Racemic

Intermediate 16 (0.148 g, 0.265 mmol) in solution in 20 mL of anH₂O/MeOH mixture (3:1) is stirred at ambient temperature under an H₂atmosphere, in the presence of 10% Pd/C (15 mg), for 2 hours 30 minutes.The reaction mixture is filtered and then concentrated in vacuo. Theresidue obtained is purified by reverse-phase chromatography using aseluant an H₂O/MeCN gradient. Example 21 (0.053 g, 0.15 mmol) is obtainedin the form of a white solid after lyophilisation with a yield of 56%.

¹H NMR: (500 MHz, D2O) δ ppm 7.29 (t, 2H), 7.2 (d, 2H), 7.2 (t, 1H),2.57 (t, 2H), 2.45 (m, 2H), 1.84 (m, 1H), 1.81/1.33 (m)+(m, 1+1H),1.78/1.29 (m)+(m, 1+1H), 1.69/1.31 (m)+(m, 1+1H), 1.68/1.27 (m)+(m,1+1H), 1.41/1.19 (m)+(m, 1+1H), 1.38 (m, 2H), 1.2 (m, 2H)

¹³C NMR: (500 MHz, D₂O) δ ppm 129.3, 128.2, 125.7, 43, 42.4, 40, 35.9,34.6, 30.4, 29.4, 27, 26.7, 25

IR (cm⁻¹): 3250-1800, 1694+1661, 1618

Elemental analysis: C=61.18 (61.18); H=7.90 (7.99); N=3.96 (3.96)

ESI/FIA/HR and MS/MS: [M+H]+=354.1837 (354.1834)

In the same manner, Examples 22 and 23 are obtained in accordance withprocedure B described hereinbefore by replacing intermediate 206 byintermediate 204.

Example 22:2-(4-Aminobutyl)-4-benzyl-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Dia 1 Racemic

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.7 (sl, 3H), 7.3 (dd, 2H), 7.2 (dd+t,3H), 2.7 (m, 2H), 2.55-2.4 (m, 2H), 1.95 (m, 1H), 1.8-13 (m, 10H),1.1-0.85 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=340.1677 (340.1677)

Elemental analysis: C=51.00 (50.33); H=5.90 (6.00); N=3.22 (3.09)

Example 23:2-(4-Aminobutyl)-4-benzyl-1-hydroxy-1-oxo-1-phosphinane-2-carboxylicAcid, Dia 2 Racemic

¹H NMR: (300 MHz, dmso-d6) δ ppm 15.8 (m, 2H), 7.95 (m, 2H), 7.25 (t,2H), 7.18 (t, 1H), 7.1 (d, 2H), 2.75 (m, 2H), 2.6-2.35 (m, 2H), 2.15 (m,1H), 1.75-1 (m, 12H)

ESI/FIA/HR and MS/MS: [M+H]+=340.1683 (340.1677).

Elemental analysis: C=60.20 (60.17); H=7.34 (7.72); N=3.96 (4.13)

Synthesis of the azaphosphinanes

Intermediate 17 was synthesised using a procedure described in theliterature by V. Gouverneur et al., J. Org. Chem. 2005, 70, 10803.

A 1M solution in THF of vinyl magnesium bromide (170 mL, 170 mmol, 2 eq)is added to a solution of ethyl dichlorophosphinate (10 mL, 84.26 mmol)in 100 mL of THF at −78° C. and under argon. Stirring is maintained for1 hour at −78° C. EtOH (30 mL) is then added dropwise and the reactionmixture is returned to ambient temperature. The reaction mixture is thenconcentrated under reduced pressure and the residue obtained is purifiedby flash chromatography on silica gel using a DCM/EtOH mixture (96:4) aseluant. Intermediate 17 (6.37 g, 43.6 mmol) is obtained in the form of acolourless oil with a yield of 52%.

¹H NMR: (400 MHz, DMSO-d₆) δ 6.1-6.4 (m, 6H), δ3.90 (q, 2H), δ1.25 (t,3H).

IR (cm⁻¹): 3500 (OH(H₂O)), 1609 (C═C), 1210 (P═O), 1032 and 935 cm⁻¹(P—O).

GC: t_(r) 5.83 min.

N-benzylamine (4.79 mL, 43.6 mmol, 1 eq.) is added in a single batch toa solution of intermediate 17 (6.37 g, 43.6 mmol) in an autoclave andunder argon. The reaction mixture is heated to 100° C., stirred for 16hours and concentrated under reduced pressure. The residue is taken upin AcOEt (100 mL), and the organic phase is washed with a saturated NaClsolution (3×100 mL) and dried over MgSO₄. The solvent is evaporated offand the residue obtained is purified by flash chromatography on silicagel using a DCM/EtOH mixture (95:5) as eluant. Intermediate 18 (8.68 g,34.3 mmol) is obtained in the form of a yellowish oil with a yield of79%.

¹H NMR: (CDCl₃, 400 MHz) δ 7.31 (m, 5H), 4.08 (m, 2H), 3.60 (s, 2H),2.98 (m, 2H), 2.64 (m, 2H), 1.97 (m, 2H), 1.85 (m, 2H), 1.35 (t, 3H).

GC: t_(r) 12.29 min.

A solution of 2M LDA (75.6 mL, 37.8 mmol, 1.5 eq) in THF is added to asolution of intermediate 18 (6.38 g, 25.19 mmol) in THF (30 mL) at −70°C. and under argon. After 15 minutes at −70° C., a solution of Boc₂O(7.68 g, 35.3 mmol, 1.4 eq) in 30 mL of THF is then added dropwise.Stirring is maintained for 90 minutes and 1.5 eq of LDA (75.6 mL, 37.8mmol) are then added dropwise. When the addition is complete, thereaction mixture is maintained at −70° C. for 90 minutes. A saturatedNH₄Cl solution (30 mL) as well as AcOEt (60 mL) are added and thereaction mixture is slowly returned to ambient temperature. The productis then extracted with AcOEt (2×150 mL). The organic phases arecombined, washed with a saturated NaCl solution (2×150 mL), dried overMgSO₄ and concentrated under reduced pressure. The residue obtained ispurified by flash chromatography on silica gel using a DCM/THF gradient(95:5 to 40:60) as eluant. Intermediate 19 (6.73 g, 19.04 mmol) isobtained in the form of a yellowish oil with a yield of 76%.

¹H NMR: (CDCl₃, 400 MHz) δ 7.35 to 7.2 (m, 5H), δ4.3 to 4.05 (m, 2H),δ3.60 (dd, 2H), δ3.3 to 2.5 (m, 5H), δ2.1 to 1.8 (m, 2H), δ1.50 (s, 9H),δ1.35 (t, 3H).

IR (cm⁻¹): 3500 (OH), 1721 (C═O), 1150 (P═O), 1032 and 935 (P—O).

MS: m/z 355 [M+1].

Procedure C: Procedure for Alkylation of Intermediate 19

60% NaH (8 mmol, 1.6 eq) at 10° C. is added in portions to a solution ofintermediate 204 to 212 (5 mmol, 1 eq) in DMSO (10 mL) under argon.Intermediate 19 (5 mmol) in solution in DMSO (5 mL) is then added to thesuspension and the mixture is stirred for 4 hours at ambienttemperature. The reaction mixture is then hydrolysed with an aqueousNH₄Cl solution (50 mL) and extracted with AcOEt (2×100 mL). The organicphase is washed with H₂O (2×100 mL), dried over MgSO₄ and concentratedin vacuo. The residue obtained is purified by flash chromatography onsilica gel using as eluant a DCM/AcOEt gradient (90:10 to 50:50).Intermediate 20a-f is obtained in the form of a mixture of 4diastereoisomers.

Procedure D: Deprotection of the Amino and Phosphinic Functions

TMSBr (7.92 mL, 60 mmol, 12 eq) is added dropwise to a solution ofintermediate 20a-f (5 mmol) in DCM (40 mL) under argon and at ambienttemperature. The mixture is stirred for 16 hours at ambient temperatureand then concentrated in vacuo. The residue is taken up in MeOH (40 mL)and stirred for 20 minutes at ambient temperature, before beingevaporated to dryness. The evaporate is dissolved in DCM (20 mL), andtrifluoroacetic acid (44.6 mL, 60 mmol, 12 eq) is added. The reactionmixture is stirred for 10 hours at ambient temperature and thenconcentrated in vacuo. The residue obtained is purified by reverse-phasechromatography using as eluant an H₂O/MeCN gradient. The final product(Examples 24 to 30) (zwitterion or TFA salt), a mixture of 2enantiomers, is obtained in the form of a white solid afterlyophilisation.

Intermediate 20a: tert-Butyl3-[3-[bis(tert-butoxycarbonyl)amino]propyl]-1-benzyl-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 20a is obtained starting from intermediates 19 and 205 inaccordance with procedure C described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.35-7.2 (m, 5H), 4 (m, 2H), 3.8 (m,2H), centred at 3.52 (AB, 2H), 3-2.25 (m, 4H), 2-1.8 (m, 4H), 1.45/1.35(2s, 27H), 1.2 (t, 3H), 1.2 (m, 2H)

Example 24:3-(3-Aminopropyl)-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 24 is obtained starting from intermediate 20a in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5 (m, 5H), centred at 4.35 (AB, 2H),3.75/3.35 (2m, 2H), 3.5/3.15 (2dd, 2H), 2.92 (t, 2H), 2.3/1.8 (2m, 2H),1.95 (m, 1H), 1.6-1.4 (m, 3H)

ESI/FIA/HR and MS/MS: [M+H]+=327.1478 (327.1473)

Elemental analysis: C=55.38 (55.21); H=6.85 (7.10); N=8.41 (8.58)

Intermediate 20b: tert-Butyl3-{4[bis(tert-butoxycarbonyl)amino]butyl}-1-benzyl-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 20b is obtained starting from intermediates 19 and 204 inaccordance with procedure C described hereinbefore.

¹H NMR: (DMSO-d6, 400 MHz) δ 7.30 (m, 5H), 3.97 (m, 2H), 3.63-3.43 (dd,2H), 3.36 (m, 2H), 2.93-2.33 (m, 2H), 2.79 to 2.47 (m, 2H), 1.93 (m,2H), 1.93 (m, 2H), 1.43 (m, 2H), 1.42 (s, 18H), 1.36 (s, 9H), 1.21 (t,3H), 0.83 (m, 2H).

IR (cm⁻¹): 1744, 1711 cm⁻¹ (C═O), 1276 cm⁻¹ (P═O).

Example 25:3-(4-Aminobutyl)-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 25 is obtained in accordance with procedure D describedhereinbefore starting from intermediate 20b.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.2 (sl, 3H), 7.3 (m, 5H), 3.7/3.5(2*(d, 1+1H), 3.05/2.4 (2*(m, 1+1H), 2.75/2.55 (2*(m, 1+1H), 2.7 (m,2H), 1.8 (m, 1H), 1.6-1.1 (m, 7H)

ESI/FIA/HR and MS/MS: [M+H]+=341.1628 (341.1630)

Elemental analysis: C=55.99 (56.46); H=7.14 (7.40); N=8.13 (8.23)

Intermediate 20c: tert-Butyl3-{5-bis(tert-butoxycarbonyl)amino]pentyl}-1-benzyl-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 20c is obtained starting from intermediates 19 and 206 inaccordance with procedure C described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.32-7.2 (m, 5H), 3.99 (m, 2H), 3.8 (m,2H), centred at 3.5 (AB, 2H), 3-2.3 (m, 4H), 2-1.8 (m, 4H), 1.45/1.35(2s, 27H), 1.35/1.15 (2m, 4H), 1.2 (t, 3H), 0.75 (m, 2H)

Example 26:3-(5-Aminopentyl)-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 26 is obtained starting from intermediate 20c in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5 (m, 5H), centred at 4.32 (AB, 2H),33/3.35 (2m, 2H), 3.5/3.1 (2dd, 2H), 2.9 (t, 2H), 2.2/1.78 (2m, 2H),1.95/1.45 (2m, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=355.1792 (355.1786)

Elemental analysis: C=58.04 (57.62); H=7.37 (7.68); N=7.95 (7.90)

Intermediate 20d: tert-Butyl1-benzyl-3-({6-[bis-tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 20d is obtained starting from intermediates 19 and 211 inaccordance with procedure C described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.18 (s, 1H), 7.4-7.25 (m, 6H), 7.18(d, 1H), 4 (m, 2H), 3.8 (m, 2H), 3.58/3.5 (2d, 2H), 3-2.6 (m, 4H),2.25/2.1 (2m, 2H), 1.4 (s, 27H), 1.2 (t, 3H)

Example 27:3-[(6-Aminopyridin-3-yl)methyl]-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 27 is obtained starting from intermediate 20d in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.51 (dd, 1H), 7.42 (d, 1H), 7.4-7.25 (m,5H), 6.75 (d, 1H), centred at 4.25 (AB, 2H), 3.78 (m, 1H), 3.4 (dd+m,2H), 2.95 (dd, 1H), 2.7 (dd, 1H), 2.6 (dd, 1H), 2.28/1.85 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=376.1418 (376.1426)

Elemental analysis: C=57.18 (57.60); H=5.82 (5.91); N=11.25 (11.19)

Example 28:3-[(2-Aminopyridin-4-yl)methyl]-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 28 is obtained starting from intermediates 19 and 212 inaccordance with procedures C and D described hereinbefore withoutintermediate purification.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (dl, 1H), 7.4 (m, 5H), 6.55 (m, 2H),4.6/4 (dd, 2H), 3.9-3.4 (m, 2H), 3.6/2.75 (dd, 2H), 3/2.7 (dd, 2H),2.3/1.9 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=376.1428 (376.1426)

Elemental analysis: C=56.70 (57.60); H=5.45 (5.91); N=10.87 (11.19)

Intermediate 20e: tert-Butyl1-benzyl-3-(3-{[bis-(tert-butoxycarbonyl)amino]methyl}-benzyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 20e is obtained starting from intermediates 19 and 208 inaccordance with procedure C described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.4-7.3 (m, 5H), 7.15 (t, 1H), 7.1 (sl,1H), 7.05/6.95 (d, 2H), 4.6 (s, 2H), 4 (m, 2H), 3.7/3.45 (dd, 2H), 3.35(m, 2H), 2.9/2.15 (m, 2H), 2.7/2.55 (dd, 2H), 2.05 (m, 2H), 1.4 (s,27H), 1.2 (t, 3H)

Example 29:3-{[3-(Aminomethyl)phenyl}methyl]-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 29 is obtained starting from intermediate 20e in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.3 (m, 5H), 7.3-7.05 (m, 4H), 4.4/195 (dd,2H), 4 (dd, 2H), 3.8-33 (m, 2H), 3.55/2.75 (dd, 2H), 3/2.7 (dd, 2H),2.2/1.8 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=389.1623 (389.1630)

Elemental analysis: C=61.37 (61.85); H=6.30 (6.49); N=7.05 (7.21)

Intermediate 20f: tert-Butyl1-benzyl-3-(4-{[bis(tert-butoxycarbonyl)amino]methyl)}-benzyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 20f is obtained starting from intermediates 19 and 209 inaccordance with procedure C described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.35 (m, 5H), 6.99 (d, 2H), 6.91 (d,2H), 4.6 (s, 2H), 3.98 (m, 2H), 3.5 (s, 2H), 3.27 (m, 2H), 2.95/2.22(2*m, 2H), 2.75/2.49 (2*m, 2H), 2.05 (m, 2H), 1.35 (2*s, 27H), 1.18 (t,3H)

¹³C NMR: (400 MHz, dmso-d6) δ ppm 152, 138, 137, 135, 130, 128, 126, 82,62, 60, 55.5, 50.5, 48.5, 34, 28, 24.5, 16

Example 30:3-{[4-(Aminomethyl)phenyl]methyl}-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 30 is obtained starting from intermediate 20f in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.2 (m, 5H), 7.1/7 (dd, 4H), 4.3/3.9 (dd,2H), 4 (m, 2H), 3.7-3.25 (m, 2H), 3.45/2.65 (dd, 2H), 2.9/2.65 (dd, 2H),2.15/1.75 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=389.1623 (389.1630)

Elemental analysis: C=61.41 (61.85); H=6.36 (6.49); N=7.40 (7.21)

Intermediate 20b: tert-Butyl3-{4[bis(tert-butoxycarbonyl)amino]butyl}-1-benzyl-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

DMSO (30 mL) and 60% NaH (8.48 g, 212 mmol, 1.5 eq) are introduced insuccession, under an argon atmosphere, into a 1 L three-necked flaskequipped with mechanical stirring. The flask is maintained at ambienttemperature by means of a water bath. A solution of intermediate 204(54.6 g, 155 mmol, 1.1 eq) in DMSO (25 mL) is then added dropwise over aperiod of 5 minutes. A solution of intermediate 19 (50 g, 141.5 mmol) inDMSO (120 mL) is then added dropwise, the temperature being maintainedbelow 20° C. When the addition is complete, 100 mL of anhydrous THF arethen added in order that stirring can be maintained. After 3 hours, thereaction mixture is cooled by means of an ice-water bath and hydrolysedby addition of 500 mL of a saturated NH₄Cl solution. The mixture is thenextracted with AcOEt (3×300 mL). The organic phases are then combined,washed with a saturated NaCl solution (2×300 mL) and dried over MgSO₄,before being concentrated under reduced pressure. The yellowish residue(92.5 g) so obtained is then purified by chromatography on silica gelusing a CH₂Cl₂/AcOEt/MeOH mixture as eluant. The expected product (69.3g, 110.9 mmol), a mixture of 4 diastereoisomers, is obtained in the formof a white solid with a yield of 78%.

Procedure E: Procedure for Debenzylation by Hydrogenolysis Intermediate21: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 20b (73.6 g, 117.8 mmol), ethanol (1 L), Pd/C (7.36 g, 10%by mass) and 37% HCl (7.85 mL, 0.8 eq) are introduced in succession intoa 2 L flask at ambient temperature and under a stream of argon. Theargon is then replaced by a hydrogen atmosphere. The reaction ismonitored by LC/MS. After 4 hours, the reaction is complete and thecatalyst is filtered off over glass fibre. The filtrate is evaporated todryness in order to obtain a yellow oil, which is taken up in AcOEt (400mL) and in a 10% NaHCO₃ solution (400 mL). After decantation, theaqueous phase is extracted with AcOEt (3×100 mL). The organic phases arecombined and then washed with a saturated NaCl Solution (400 mL), driedover MgSO₄ and concentrated to yield the expected intermediate 21 in theform of a white solid (57.6 g, 107.7 mmol) with a yield of 91%.

¹H NMR: (DMSO-d₆, 400 MHz) δ 4.05 to 3.85 (m, 2H), 3.45 (m, 2H), 3.1 to2.6 (m, 4H), 2.3-1.7 (m, 4H), 1.45 (s, 18H), 1.40 (s, 9H), 1.20 (t, 3H),1.5-0.9 (m, 4H).

IR (cm⁻¹): 3100-3500 cm⁻¹ (OH), 3314 cm⁻¹ (NH), 1712-1693 cm⁻¹ (C═O).

Procedure L: Procedure for Synthesis of the Aldehydes Ar₂-Ar₁—CHO by aSuzuki Coupling

The non-commercial aldehydes were prepared in accordance with theprocedure described below:

Ethanol (500 mL), boronic acid Ar₂—B(OH)₂ (92.7 mmol, 1.2 eq) andbromoarylaldehyde or bromoheteroarylaldehyde Br-An-CHO (77.3 mmol) areintroduced in succession into a 1 L flask under argon and at ambienttemperature. The solution is degassed with argon for 15 minutes.Pd(PPh₃)₄ (1.78 g, 1.55 mmol) and Na₂CO₃ (92.7 mL of a 2M solution inH₂O, 185 mmol, 2.4 eq) are then introduced in a single portion. Afterthe addition, the reaction mixture is heated at reflux for 5 hours. Themixture is then evaporated to dryness. The residue is taken up in DCM (1L) and H₂O (200 mL). After decantation, the aqueous phase is extractedwith DCM (200 mL). The organic phases are combined and then washed witha saturated NaCl solution (400 mL), dried over MgSO₄ and concentratedunder reduced pressure. The residue is then purified by flashchromatography on silica gel. The expected product is obtained withyields of from 59 to 94%.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.89 (s, 1H), 7.94 (dd, 1H), 7.77 (td,1H), 7.63 (tl, 1H), 7.54 (dl, 1H), 7.54/7.4 (2m, 4H)

¹H NMR: (400/500 MHz, dmso-d6) δ ppm 9.72 (s, 1H), 7.96 (d, 1H), 7.79(t, 1H), 7.65 (t, 1H), 7.6 (t, 1H), 7.48 (m, 3H), 7.4 (d, 1H)

¹H NMR: (400/500 MHz, dmso-d6) δ ppm 9.91 (s, 1H), 7.95 (d, 1H), 7.78(m, 1H), 7.78 (m, 1H), 7.74 (d, 1H), 7.64 (t, 1H), 7.53 (d, 1H), 7.44(dd, 1H)

DEI (70 eV): [M]+.=250

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.59 (s, 1H), 9.43 (s, 1H), 8.46 (d,1H), 8.26 (d, 1H), 8.06 (d, 1H), 7.85 (t, 1H), 7.81 (t, 1H), 7.77 (d,1H), 7.74 (t, 1H), 7.51 (d, 1H), 7.24 (d, 1H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.2 (s, 1H), 8.1 (dd, 1H), 7.85 (m, 2H),7.4 (m, 2H), 7.3 (dd+s, 2H), 7.2 (td, 1H)

¹⁹F NMR: (400 MHz, CDCl3) δ ppm −101.1

GC-EI (70 eV): [M]+.=256

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.25 (s, 1H), 8.8 (d, 1H), 8 (m, 1H),7.85 (m, 1H), 7.85/7.75 (2m, 2H), 7.05 (d, 1H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.05 (s, 1H), 9.2 (s, 1H), 8.05 (m,2H), 7.7 (m, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.81 (s, 1H), 8.02 (dd, 1H), 7.58/7.52(2d, 4H), 7.46 (td, 1H), 7.4 (dd, 1H)

GC-EI (70 eV): [M]+.=234

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.82 (s, 1H), 7.97 (dd, 1H), 7.42 (d,2H), 7.38 (td, 1H), 7.35 (dd, 1H), 7.09 (d, 2H), 3.83 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.82 (s, 1H), 7.99 (dd, 1H), 7.42 (m,3H), 7.08/7.01 (2dl, 2H), 7.06 (sl, 1H), 3.82 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 99 (s, 1H), 7.92 (dd, 1H), 7.78 (td,1H), 7.69 (dd, 1H), 7.65 (dd, 1H), 7.38 (d, 1H), 7.07 (d, 1H), 3.68 (s,3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.8 (sl, 1H), 7.68 (dd, 1H), 7.62 (m,2H), 7.54 (m, 3H), 7.5 (d, 1H)

GC-EI (70 eV): [M]+.=188

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.35 (s, 1H), 8.07 (d, 1H), 7.99 (d,1H), 7.88 (m, 2H), 7.79/7.67 (2*t, 2H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1H), 7.95 (d, 1H), 7.8 (m, 1H),7.65 (m, 1H), 7.5 (d, 1H), 6.85 (s, 1H), 3.4 (s, 3H), 2.4 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.85 (s, 1H), 8.15 (m, 1H), 8.06 (m,1H), 7.85 (m, 1H), 7.74 (s, 1H), 7.7 (m, 1H), 7.7 (m, 1H), 7.7 (m, 1H),7.35 (m, 1H), 6.95 (m, 1H)

¹H NMR: (400/500 MHz, dmso-d6) δ ppm 9.53 (s, 1H), 8.08 (d, 1H), 8.08(d, 1H), 8.02 (dd, 1H), 7.83 (td, 1H), 7.71 (tt, 1H), 7.63 (dd, 1H),7.57 (td, 1H), 7.51 (d, 1H), 7.49 (d, 1H), 7.49 (td, 1H), 7.38 (dt, 1H)

¹³C NMR: (400/500 MHz, dmso-d6) δ ppm 192, 143.5, 135.5, 135, 134, 133,132, 128.5, 128.5, 128, 128, 127, 127, 126.5, 125.5, 125

¹H NMR: (400 MHz, CDCl3) δ ppm 9.9 (s, 1H), 8.05 (dd, 1H), 7.15 (m, 2H),7 (d, 1H), 6.9 (m, 2H), 3.95 (2 s, 6H)

DEI (70 eV): [M]+.=260

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.8 (sl, 1H), 9.7 (s, 1H), 8.2 (d,1H), 723 (d, 1H), 7.79 (dd, 1H), 6.95 (dd, 1H), 6.91 (d, 1H), 6.77 (d,1H), 3.9 (s, 3H)

¹H NMR: (400 MHz, CDCl3) δ ppm 10.2 (s, 1H), 8 (dd, 1H), 7.75 (t, 1H),7.4 (dd, 1H), 7.2 (m, 2H), 6.8 (d, 1H), 3.95 (s, 3H)

GC-EI (70 eV): [M]+.=231

¹H NMR: (400 MHz, CDCl3) δ ppm 10.5 (m, 1H), 8.1 (dd, 1H), 8 (m, 1H),7.5 (d, 1H), 7.4 (dd, 1H), 7.25 (td, 1H)

GC-EI (70 eV): [M]+.=207

¹H NMR: (400 MHz, dmso-d6) δ ppm 10 (s, 1H), 8.65 (s, 1H), 8.06 (m, 2H),7.6 (m, 3H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.8 (s, 1H), 8.2 (dd, 1H), 8 (d, 1H), 7.8(d, 1H), 7.75 (s, 1H), 7.3 (m, 3H), 6.95 (t, 1H)

GC-EI (70 eV): [M]+.=240

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.15 (d, 1H), 8.05 (s, 1H), 7.86 (dd,1H), 7.7 (d, 1H), 7.68 (td, 1H), 7.53 (dd, 1H), 7.46 (td, 1H), 3.91 (s,3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 10 (s, 1H), 9.25 (s, 1H), 8.91 (s, 2H),8.05 (dd, 1H), 7.83 (td, 1H), 7.73 (td, 1H), 7.58 (dd, 1H)

¹H NMR: (300 MHz, dmso-d6) δ ppm 9.9 (s, 1H), 8.25 (s, 1H), 7.95 (d,1H), 7.85 (dd, 1H), 7.75/7.6 (2*m, 2H), 7.55 (d, 1H), 6.95 (d, 1H), 3.9(s, 3H)

¹H NMR: (400/500 MHz dmso-d6) δ ppm 9.64 (s, 1H), 7.68 (d, 1H), 7.63 (t,1H), 7.57 (t, 1H), 7.51 (t, 1H), 7.47 (d, 1H), 7.45 (t, 1H), 7.42 (d,1H), 7.34 (d, 1H), 7.17/7.03 (2*m, 5H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1H), 8 (d, 1H), 7.8 (t, 1H),7.69 (t, 1H), 7.6 (d, 1H), 7.55 (m, 2H), 7.4 (d, 1H)

GC-EI (70 eV): [M]+.=250

¹H NMR: (400/500 MHz, dmso-d6) δ ppm 9.95 (s, 1H), 8.07 (d, 1H), 8.02(m, 2H), 7.99 (d, 1H), 7.98 (dd, 1H), 7.8 (td, 1H), 7.64 (d, 1H), 7.62(td, 1H), 7.62 (m, 1H), 7.6 (m, 2H)

¹³C NMR: (400/500 MHz, dmso-d6) δ ppm 192, 134, 131.5, 129, 128, 128,128, 128, 127.5, 127

¹H NMR: (400/500 MHz, dmso-d6) δ ppm 9.98 (s, 1H), 7.95 (dd, 1H), 7.78(m, 1H), 7.78 (m, 1H), 7.75 (d, 2H), 7.72 (t, 1H), 7.63 (d, 1H), 7.62(t, 1H), 7.61 (t, 1H), 7.49 (t, 2H), 7.44 (dt, 1H), 7.4 (t, 1H)

¹³C NMR: (400/500 MHz, dmso-d6) δ ppm 192, 145.5, 140, 134, 133.5, 131,129, 129, 128, 128, 128, 127.5, 127, 127, 127

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.77 (s, 1H), 8.05 (dd, 1H), 7.82 (td,1H), 7.7 (td, 1H), 7.6 (d, 2H), 7.5 (t, 1H), 7.35 (dd, 1H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1H), 9.25 (s, 1H), 8.95 (s,2H), 8.15 (dd, 1H), 7.55 (m, 2H)

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −102.8

¹H NMR: (400 MHz, CDCl3) δ ppm 10 (s, 1H), 8.25 (dd, 1H), 8.05 (dd, 1H),7.7 (td, 1H), 7.55 (td, 1H), 7.4 (dd, 1H), 6.9 (dd, 1H), 6.75 (dd, 1H),4 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.7 (s, 1H), 7.9 (dd, 1H), 7.75 (td,1H), 7.58 (t, 1H), 7.43 (d, 1H), 7.25-7.15 (m, 2H), 6.91 (dd, 1H), 3.87(s, 3H), 3.38 (s, 3H)

¹H NMR: (300/400/500 MHz, dmso-d6) δ ppm 10.03 (s, 1H), 7.98 (dd, 1H),7.83 (dd, 1H), 7.46 (dd, 1H), 7.43 (td, 1H), 7.36 (dd, 1H), 7.25 (dd,1H)

¹³C NMR: (300/400/500 MHz, dmso-d6) δ ppm 190.2, 165, 140.3, 137.3,131.2, 130.7, 130.6, 129, 128.4, 117.8, 115.9

¹⁹F NMR: (300/400/500 MHz, dmso-d6) δ ppm −103

¹H NMR: (300/400/500 MHz, dmso-d6) δ ppm 9.9 (s, 1H), 8.06 (s, 1H), 8.05(d, 1H), 8.04-8.02 (m, 3H), 7.64 (dd, 1H), 7.61 (td, 2H), 7.51-7.47 (m,2H)

¹³C NMR: (300/400/500 MHz, dmso-d6) δ ppm 190.4, 165, 148.3, 131.2,130.6, 129.5-128.2, 128.2, 127.7, 127.1, 117.9/115.5

¹⁹F NMR: (300/400/500 MHz, dmso-d6) δ ppm −103.2

¹H NMR: (400 MHz, CDCl3) δ ppm 9.88 (s, 1H), 8.1 (dd, 1H), 7.74 (s, 1H),7.29 (td, 1H), 7.14 (s, 1H), 7.1 (dd, 1H), 3.56 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.84 (s, 1H), 8.27 (d, 1H), 8.04 (dd,1H), 7.5 (td, 1H), 7.43 (dd, 1H), 7.1 (dd, 1H), 6.96 (s, 1H), 3.91 (s,3H)

¹⁹F NMR: (400 MHz, CDCl3) δ ppm −101.2

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.1 (s, 1H), 8.12 (d, 1H), 7.93 (d,1H), 7.78 (dd, 1H), 7.39 (dd, 1H), 7.3 (td, 1H), 3.91 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.76 (s, 1H), 7.98 (dd, 1H), 7.79 (td,1H), 737 (d, 1H), 7.68 (td, 1H), 7.56 (dd, 1H), 7.47 (d, 1H), 7.39 (dd,1H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.84 (s, 1H), 8.59 (d, 1H), 7.69 (d,1H), 7.5-7.3 (m, 5H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.64 (s, 1H), 8.04 (dd, 1H), 7.62 (d,1H), 7.5 (m, 1H), 7.5 (m, 3H), 7.32 (dd, 1H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1H), 8 (dd, 1H), 7.45 (m, 3H),7.15 (m, 2H), 7.1 (dd, 1H), 5.25 (s, 2H), 3.4 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.75 (s, 1H), 9.95 (s, 1H), 7.85 (d,1H), 7.75 (d, 1H), 7.25 (d, 1H), 7.2 (d, 1H), 6.95 (dd, 1H), 6.9 (s, 1H)

GC-EI (70 eV): [M]+=204

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.6 (s, 1H), 9.7 (s, 1H), 7.8 (d, 1H),7.05 (d, 1H), 7 (s, 1H), 6.9 (m, 2H), 6.8 (s, 1H), 3.8 (2s, 6H)

¹H NMR: (300 MHz, CDCl3) δ ppm 9.9 (s, 1H), 8.09 (dd, 1H), 7.5/7.4(unresolved peak, 5H), 7.21 (dd, 1H), 7.15 (dd, 1H)

¹⁹F NMR: (300 MHz, CDCl3) δ ppm −103.7

¹H NMR: (400 MHz, CDCl3) δ ppm 10 (s, 1H), 8.73 (d, 2H), 8.08 (dd, 1H),7.71 (dt, 1H), 7.61 (dt, 1H), 7.42 (dd, 1H), 7.35 (d, 2H)

¹H NMR: (400 MHz, CDCl3) δ ppm 10.1 (d, 1H), 8 (dd, 1H), 7.62 (dt, 1H),7.48 (2*m, 2H), 7.46 (dd, 1H), 7.3 (dd, 1H), 7.2 (dd, 1H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.99 (s, 1H), 8.71 (dd, 1H), 8.67 (d,1H), 8.07 (dl, 1H), 7.75 (dt, 1H), 7.7 (tl, 1H), 7.59 (tl, 1H), 7.44(dd, 1H), 7.43 (dl, 1H)

¹H NMR: (300 MHz, CDCl3) δ ppm 9.9 (d, 1H), 8.74 (dd, 1H), 8.69 (dd,1H), 8.12 (dd, 1H), 7.74 (ddd, 1H), 7.47 (ddd, 1H), 7:28 (m, 1H), 7.15(dd, 1H)

¹⁹F NMR: (300 MHz, CDCl3) δ ppm −102.6

¹H NMR: (400 MHz, CDCl3) δ ppm 9.89 (s, 1H), 8.75 (d, 2H), 8.11 (dd,1H), 7.33 (d, 2H), 7.27 (td, 1H), 7.12 (dd, 1H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.82 (s, 1H), 8.01 (d, 1H), 7.45 (m, 3H),7.38 (m, 2H), 6.94 (dd, 1H), 6.85 (df, 1H), 5.72 (sl, 1H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.68 (s, 1H), 9.35 (s, 1H), 8.5 (s, 1H),8.15 (dd, 1H), 8.1 (m, 1H), 7.75 (dt, 1H), 7.67 (2*m, 2H), 7.65 (dt,1H), 7.51 (m, 1H), 7.47 (dd, 1H)

GC-EI (70 eV): [M]+.=233.1

¹H NMR: (300 MHz, CDCl3) δ ppm 9.9 (sl, 1H), 8.03 (dd, 1H), 7.24 (d,2H), 7.12 (td, 1H), 7.1 (dd, 1H), 6.95 (d, 2H), 5.3 (s, 1H)

¹⁹F NMR: (300 MHz, CDCl3) δ ppm −102.4

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.65 (s, 1H), 9.65 (s, 1H), 7.8 (d,1H), 7.3 (s, 4H), 6.9 (dd, 1H), 6.75 (s, 1H), 2.35 (d, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1H), 8.2 (d, 1H), 8.05 (d, 1H),7.75 (s, 1H), 7.7 (d, 1H), 7.35 (t, 1H), 7.25 (dd, 1H), 7.2 (s, 1H),6.95 (t, 1H), 3.9 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.75 (s, 1H), 8.69 (d, 2H), 7.97 (d,1H), 7.7 (dd, 1H), 7.5 (d, 2H), 7 (d, 1H), 3.9 (s, 3H)

¹H NMR: (300/400 MHz, dmso-d6) δ ppm 9.8 (s, 1H), 8 (dd, 1H), 7.55 (m,1H), 7.5 (m, 1H), 7.45 (d, 1H), 7.45 (d, 1H), 7.35 (m, 1H), 7.3 (dd, 1H)

¹⁹F NMR: (300/400 MHz, dmso-d6) δ ppm −103.1, −111.7

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.75 (sl, 1H), 9.65 (s, 1H), 7.81 (d,1H), 7.45 (dd, 2H), 7.3 (dd, 2H), 6.93 (dd, 1H), 6.75 (d, 1H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.88 (s, 1H), 8.06 (dd, 1H), 7.36 (dd,2H), 7.19 (m, 1H), 7.19 (dd, 2H), 7.11 (dd, 1H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.9 (s, 1H), 8.05 (dd, 1H), 7.28 (dd,4H), 7.16 (td, 1H), 7.12 (dd, 1H), 2.44 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.82 (s, 1H), 8 (dd, 1H), 7.48-7.3 (m,2H), 7.48-7.3 (m, 2H), 7 (ddd, 1H), 3.9 (s, 3H)

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −104.4, −135.7

¹H NMR: (400 MHz, dmso-d6) δ ppm 9:8 (s, 1H), 8.05 (dd, 1H), 7.45 (m,1H), 7.4 (d, 1H), 6.9 (s, 1H), 3.45 (s, 3H), 2.35 (s, 3H)

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −102.9

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.7 (s, 1H), 7.95 (d, 1H), 7.15 (dd,1H), 7 (s, 1H), 6.85 (s, 1H), 3.9 (s, 3H), 3.4 (s, 3H), 2.35 (s, 3H)

¹H NMR: (300/400 MHz, dmso-d6) δ ppm 9.7 (s, 1H), 7.93 (d, 1H), 7.8 (s,1H), 7.18 (dd, 1H), 7.03 (d, 1H), 7 (s, 1H), 3.9 (s, 3H), 3.54 (s, 3H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.85 (s, 1H), 8.15 (dd, 1H), 7.6 (s, 1H),7.3 (m, 1H), 7.15 (d, 1H), 6.35 (s, 1H), 3.75 (s, 3H)

¹⁹F NMR: (400 MHz, CDCl3) δ ppm −101.2

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1H), 7.98 (dd, 1H), 7.9 (d,1H), 7.84 (d, 1H), 7.78 (td, 1H), 7.77 (dd, 1H), 7.67 (tl, 1H), 7.55(dd, 1H)

DEI (70 eV): [M]+.=284

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1H), 7.9 (d, 1H), 7.75 (m, 1H),7.55 (m, 1H), 7.5 (d, 1H), 7.1 (s, 1H), 7.05 (d, 1H), 6.85 (dd, 1H), 6.1(s, 2H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.8 (s, 1H), 7.99 (d, 1H), 7.8 (t, 1H),7.69 (t, 1H), 7.58 (d, 1H), 7.55 (d, 1H), 6.41 (d, 1H), 3.69 (s, 3H)

¹³C NMR: (400 MHz, dmso-d6) δ ppm 191, 138, 138, 136, 134, 133, 132,130, 128, 109, 37

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.9 (s, 1H), 7.91 (d, 1H), 7.75 (t,1H), 7.59 (t, 1H), 7.54 (d, 1H), 7.42 (t, 1H), 7.05 (dd, 1H), 7.01 (t,1H), 6.98 (dd, 1H), 3.82 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.66 (s, 1H), 7.86 (d, 1H), 7.73 (t,1H), 7.54 (t, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 7.14 (d,1H), 7.11 (t, 1H), 3.69 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.86 (s, 1H), 8.17 (d, 1H), 738 (d,1H), 7.7-7.55 (m, 1H), 7.7-7.55 (m, 5H), 7.52 (t, 1H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.82 (d, 1H), 8.17 (dd, 1H), 7.62 (d,2H), 7.52 (m, 3H), 7.43 (d, 1H)

¹H NMR: (400 MHz, CDCl3) δ ppm 9.85 (s, 1H), 8.03 (d, 1H), 7.5-7.37 (m,5H), 7 (dd, 1H), 6.89 (df, 1H), 3.9 (s, 3H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.89 (s, 1H), 7.95 (d, 1H), 7.77 (t,1H), 7.62 (m, 3H), 7.53 (d, 1H), 7.49 (d, 2H)

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −55, 59

¹H NMR: (400 MHz, CDCl3) δ ppm 9.9 (d, 1H), 8.04 (dd, 1H), 7.68 (dt,1H), 7.56 (t, 1H), 7.39 (d, 1H), 7.31 (dt, 1H), 7.01 (dt, 1H), 6.95 (dt,1H)

¹⁹F NMR: (400 MHz, CDCl3) δ ppm −109/−110

¹H NMR: (400 MHz, CDCl3) δ ppm 10 (d, 1H), 8.01 (dd, 1H), 7.63 (dt, 1H),7.48 (t, 1H), 7.44 (d, 1H), 7.29 (s, 4H), 2.43 (s, 3H)

¹H NMR: (400 MHz, CDCl3) δ ppm 10 (s, 1H), 8.02 (d, 1H), 7.62 (t, 1H),7.45 (d, 1H), 7.32 (2*d, 4H), 4.48 (t, 1H), 2.99 (hept., 1H), 1.31 (d,6H)

¹H NMR: (400 MHz, CDCl3) δ ppm 10.27 (d, 1H), 7.99 (dd, 1H), 7.61 (dt,1H), 7.55 (2*m, 2H), 7.46 (2*m, 2H), 6.59 (dd, 1H)

¹H NMR: (300 MHz, dmso-d6) δ ppm 9.99 (s, 1H), 8.86 (d, 1H), 8.82 (df,1H), 7.79 (dd, 1H), 7.6 (2*d, 4H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.85 (s, 1H), 7.95 (d, 1H), 7.65 (dd,1H), 7.6 (s, 1H), 7.55 (d, 2H), 7.5 (d, 2H)

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.7 (s, 1H), 8 (dd, 1H), 7.8 (td, 1H),7.7 (td, 1H), 7.65 (d, 1H), 7.55 (dd, 1H), 6.5 (d, 1H), 5 (dd, 1H),3.8/3.25 (2m, 2H), 2.25/1.8 (2m, 2H), 1.9/1.5 (2m, 2H), 1.4 (m, 2H)

Procedure F: Generic Procedure for Reductive Amination Starting fromIntermediate 21 (Synthesis of Intermediates 22 to 127)

Intermediate 21 (14 g, 26.2 mmol), anhydrous DCM (280 mL), the aldehyde(intermediates 213 to 293) (39.3 mmol, 1.5 eq) and MgSO₄ (14 g) areintroduced in succession into a 500 mL three-necked flask at ambienttemperature and under a stream of argon. After stirring for 1 hour,NaBH(OAc)₃ (8.32 g, 39.3 mmol, 1.5 eq) is added in portions and thereaction mixture is maintained at ambient temperature for 16 hours. Thereaction is monitored by LC/MS. The insoluble components are filteredoff over microfibre and rinsed with DCM (100 mL). The filtrate is thenwashed with water (1×200 mL) and then with a saturated NaCl solution(2×200 mL). The organic phase is dried over MgSO₄ and concentrated underreduced pressure. The oil obtained is then purified by flashchromatography on silica gel (330 g) to yield intermediates 22 to 127.

Example 31:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylic Acid

Example 31 is obtained starting from intermediate 21 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 3.5-3.65 (2m, 2H), 3.2 (m, 1H), 3.05 (dd,1H), 2.95 (m, 2H), 2.15 (m, 1H), 1.95 (m, 1H), 1.75 (m, 1H), 1.65 (m,2H), 1.5 (m, 1H), 1.4 (m, 1H), 1.25 (m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=251.1154 (251.1160)

Elemental analysis: C=42.65 (43.20); H=7.23 (7.65); N=11.24 (11.20)

Intermediate 22: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(3-fluoro-4-hydroxyphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 22 is obtained starting from intermediate 21 and3-fluoro-4-hydroxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.0 (d, 1H), 6.88 (d, 2H), 3.95 (m,2H), 3.5/3.33 (2*d, 2H), 3.4 (m, 2H), 2.85/2.3 (2*m, 2H), 2.8/2.45 (dd,2H), 2-1.6 (m, 4H), 1.42/1.35 (2*s, 27H), 1.4 (m, 2H), 1.2 (t, 3H), 0.9(m, 2H)

Example 32:3-(4-Aminobutyl)-1-[(3-fluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 32 is obtained starting from intermediate 22 in accordance withprocedure D described hereinbefore.

¹H NMR: (300/400 MHz, D2O) δ ppm 7.24 (dd, 1H), 7.12 (dd, 1H), 7.03 (t,1H), 4.32/4.12 (2*d, 2H), 3.68/3.3 (2*m, 2H), 3.45/3.07 (2*m, 2H), 2.92(m, 2H), 2.22/1.78 (2*m, 2H), 1.92/1.58 (2*m, 2H), 1.58/1.46 (2*m, 2H),1.23/1.1 (2*m, 2H)

¹⁹F NMR: (300/400 MHz, D2O) δ ppm −135.8

ESI/FIA/HR and MS/MS: [M+H]+=375.1455 (375.1480)

Elemental analysis: C=51.71 (51.34); H=6.44 (6.46); N=7.64 (7.48)

Intermediate 23: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(2,4-difluorophenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 23 is obtained starting from intermediate 21 and2,4-difluorobenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.44 (m, 1H), 7.19 (m, 1H), 7.07 (m,1H), 4 (m, 2H), 3.57 (m, 2H), 3-2.6/2.35 (m, 2), 3-2.6/2.52 (m, 2H),2.78 (m, 2H), 2-1.6 (m, 2H), 2-1.6 (m, 2H), 1.39 (m, 27H), 1.39 (m, 2H),1.2 (m, 3H), 0.82 (m, 2H)

Example 33:3-(4-Aminobutyl)-1-[(2,4-difluorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 33 is obtained starting from intermediate 23 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.51 (m, 1H), 7.07 (m, 2H), 4.37 (sl, 2H),3.69/3.33 (m, 2H), 3.49/3.19 (m, 2H), 2.95 (m, 2H), 2.21/1.77 (m, 2H),1.95/1.49 (m, 2H), 1.61 (m, 2H), 1.28/1.14 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=377.1419 (377.1441)

Elemental analysis: C=50.66 (51.06); H=5.79 (6.16); N=7.37 (7.44)

Intermediate 24: tert-Butyl3-{4-[Bis(tert-butoxycarbonyl)amino]butyl}-1-[(3,5-difluoro-4-hydroxyphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 24 is obtained starting from intermediate 21 and3,5-difluoro-4-hydroxy-benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 10.1 (sl, 1H), 6.63 (d, 2H), 4.1-3.8(m, 2H), 3.58-3.3 (m, 2H), 3.58-3.3 (m, 2H), 3-2.6/2.3 (2*m, 2H),3-2.6/2.49 (2*m, 2H), 2-1.5 (m, 2H), 2-1.5 (m, 2H), 1.4 (m, 2H),1.4/1.37 (2*s, 27H), 1.2 (t, 3H), 1.1-0.8 (m, 2H)

Example 34:3-(4-Aminobutyl)-1-[(3,5-difluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 34 is obtained starting from intermediate 24 in accordance withprocedure D described hereinbefore.

¹H NMR: (300/400 MHz, D2O) δ ppm 7.1 (m, 2H), 4.33/4.12 (2*d, 2H),3.69/3.31 (2*dd, 2H), 3.45/3.09 (2*dd, 2H), 2.94 (m, 2H), 2.24/1.78(2*m, 2H), 1.93/1.6 (2*m, 2H), 1.6/1.47 (2*m, 2H), 1.25/1.13 (2*m, 2H)

¹⁹F NMR: (300/400 MHz, D2O) δ ppm −132

ESI/FIA/HR and MS/MS: [M+H]+=393.1388 (393.1390)

Elemental analysis: C=48.74 (48.98); H=5.90 (5.91); N=7.10 (7.14)

Intermediate 25: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[4-(difluoromethyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 25 is obtained starting from intermediate 21 and4-(difluoromethyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.55-7.4 (dd, 4H), 7 (t, 1H), 4.1-3.85(m, 2H), 3.7-3.5 (dd, 2H), 3.35 (m, 2H), 3-2.25 (m, 4H), 2-1.8 (m, 4H),1.4 (m, 2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.2 (t, 3H), 0.8 (m, 2H).

Example 35:3-(4-Aminobutyl)-1-{[4-(difluoromethyl)phenyl}methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 35 is obtained starting from intermediate 25 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7-7.6 (d, 4H), 6.85 (t, 1H), 4.5/4.3 (m,2H), 3.8-3.65 (m, 1H), 3.55-3.35 (m, 2H), 3.15 (m, 1H), 2.95 (m, 2H),2.25 (m, 1H), 2-1.75 (m, 2H), 1.65-1.5 (m, 3H), 1.3-1.1 (m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 26

¹⁹F NMR: (400 MHz, D2O) δ ppm −110

ESI/FIA/HR and MS/MS: [M+H]+=391.1583 (391.1598)

Elemental analysis: C=51.85 (52.31); H=6.46 (6.45); N=7.04 (7.18)

Intermediate 26: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-hydroxy-3-(trifluoromethyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 26 is obtained starting from intermediate 21 and4-hydroxy-3-(trifluoromethyl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.45 (unresolved peak, 1H), 7.4 (sl,1H), 7.34 (dl, 1H), 6.96 (d, 1H), 4.1-3.85 (m, 2H), 3.65-3.3 (m, 2H),3.65-3.3 (m, 2H), 3-2.2 (m, 4H), 2-1.6 (m, 4H), 1.38 (m, 29H), 1.2 (t,3H), 0.88 (m, 2H)

Example 36:3-(4-Aminobutyl)-4-hydroxy-1-[[4-hydroxy-3-(trifluoromethyl)phenyl]-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 36 is obtained starting from intermediate 26 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.68 (df, 1H), 7.55 (dd, 1H), 7.09 (d, 1H),4.38/4.2 (2*d, 2H), 3.7/3.3 (2*dd, 2H), 3.45/3.09 (2*dd, 2H), 2.92 (m,2H), 2.23/1.77 (2*m, 2H), 1.93/1.6 (2*m, 2H), 1.6/1.47 (2*m, 2H),1.25/1.11 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=425.1453 (425.1453)

Elemental analysis: C=48.19 (48.12); H=5.16 (5.70); N=6.72 (6.60)

Intermediate 27: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(3-chloro-5-fluoro-4-hydroxyphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 27 is obtained starting from intermediate 21 and3-chloro-5-fluoro-4-hydroxybenzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.26 (sl, 1H), 7.12 (sl, 1H), 7.07(dl, 1H), 4:06/3.98 (2quad, 2H), 3.47 (AB, 2H), 3.42 (m, 2H), 3-2.26 (m,4H), 1.94 (m, 4H), 1.41/1.37 (2s, 27H), 1.4 (m, 2H), 1.25/1.21 (2t, 3H),0.92 (m, 2H)

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −131.7

³¹P NMR: (400 MHz, dmso-d6) δ ppm −43

ESI/FIA/HR and MS/MS: [M+H]+=693.308 (693.3083)

Example 37:3-(4-Aminobutyl)-1-[(3-chloro-5-fluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 37 is obtained starting from intermediate 27 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.3 (m, 1H), 7.21 (m, 1H), 4.31/4.12 (2*d,2H), 3.69/3.3 (2*dd, 2H), 3.45/3.09 (2*dd, 2H), 2.93 (m, 2H), 2.24/1.77(2*m, 2H), 1.93/1.6 (2*m, 2H), 1.6/1.47 (2*m, 2H), 1.27/1.13 (2*m, 2H)

¹⁹F NMR: (400 MHz, D2O) δ ppm −131.6

ESI/FIA/HR and MS/MS: [M+H]+=409.1091 (409.1095)

Elemental analysis: C=47.25 (47.01); H=5.75 (5.67); N=6.92 (6.85)

Intermediate 28: tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 28 is obtained starting from intermediate 21 and2,3-dihydrobenzofuran-5-carbaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.13 (d, 1H), 6.97 (dd, 1H), 6.68 (d,1H), 4.5 (t, 2H), 4 (m, 2H), 3.55-3.3 (m, 4H), 3.15 (m, 2H), 3-2.2 (m,4H), 1.91 (m, 4H), 1.39 (m, 29H), 1.2 (t, 3H), 0.87 (m, 2H)

Example 38:3-(4-Aminobutyl)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 38 is obtained starting from intermediate 28 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.34 (d, 1H), 7.2 (dd, 1H), 6.85 (d, 1H),4.59 (t, 2H), 4.14/3.68 (dd, 2H), 3.68/3.28 (m, 2H), 3.47/3.06 (m, 2H),3.22 (t, 2H), 2.94 (m, 2H), 2.22/1.76 (m, 2H), 1.93/1.47 (m, 2H), 1.6(m, 2H), 1.26/1.12 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=383.1725 (383.1735)

Elemental analysis: C=55.92 (56.54); H=6.71 (7.12); N=7.17 (7.33)

Intermediate 29: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-oxo-3H-1,3-benzoxazol-6-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 29 is obtained starting from intermediate 21 and3H-1,3-benzoxazole-carbaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 12.55 (s, 1H), 7.15 (s, 1H), 7.05 (dd,1H), 7 (d, 1H), 4 (m, 2H), 3.65 (d, 1H), 3.4 (d, 1H), 3.35 (m, 2H),3.05-2.3 (m, 4H), 2.05-1.8 (m, 4H), 1.4 (m, 2H), 1.4 (3s, 27H), 1.25 (t,3H), 0.9-0.7 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=682.3461 (682.3468)

Example 39:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-oxo-3H-1,3-benzoxazol-6-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 39 is obtained starting from intermediate 29 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.4 (s, 1H), 7.3 (dd, 1H), 7.25 (d, 1H),4.45/4.25 (2dd, 2H), 3.8-3.6 (m, 1H), 3.45 (m, 1H), 3.35 (m, 1H), 3.1(m, 1H), 2.95 (m, 2H), 2.25 (m, 2H), 1.95 (m, 1H), 1.65-1.4 (m, 3H),1.25/1.1 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=398.1455 (398.1480)

Elemental analysis: C=51.17 (51.39); H=5.85 (6.09); N=10.49 (10.57)

Intermediate 30: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-(1H-benzimidazol-5-ylmethyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 30 is obtained starting from intermediate 21 and1H-benzimidazole-5-carbaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 12.4 (sl, 1H), 8.16 (s, 1H), 7.7-7.3(m, 2H), 7.14 (d, 1H), 3.97 (m, 2H), 3.72/3.54 (2*d, 2H), 3.45-3.2 (m,2H), 2.97/2.33 (2*m, 2H), 2.85/2.48 (2*m, 2H), 2.02-1.85 (m, 2H),2.02-1.85 (m, 2H), 1.39/1.34 (2*s, 27H), 1.38 (m, 2H), 1.2 (t, 3H), 0.81(m, 2H)

Example 40:3-(4-Aminobutyl)-1-(1H-benzimidazol-5-ylmethyl)-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 40 is obtained starting from intermediate 30 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.26 (s, 1H), 7.77 (df, 1H), 7.72 (d, 1H),7.38 (dd, 1H), 4.53/4.34 (2*d, 2H), 3.73/3.36 (2*m, 2H), 3.47/3.12 (2*m,2H), 2.88 (m, 2H), 2.23/1.78 (2*m, 2H), 1.91/1.55 (2*m, 2H), 1.55/1.45(2*m, 2H), 1.18/1.04 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=381.1692 (381.1691)

Elemental analysis: C=54.46 (53.68); H=6.00 (6.62); N=14.67 (14.73)

Intermediate 31: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(2-fluoro-4-hydroxyphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 31 is obtained starting from intermediate 21 and2-fluoro-4-methoxy-benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.25 (t, 1H), 6.78 (2*m, 2H), 4.1-3.9(m, 2H), 3.76 (s, 3H), 3.57/3.46 (2*d, 2H), 3.36 (m, 2H), 2.93/2.32(2*m, 2H), 2.81/2.47 (2*dd, 2H), 2-1.8 (m, 2H), 2-1.8 (m, 2H), 1.42/1.36(2*s, 27H), 1.4 (m, 2H), 1.2 (t, 3H), 1-0.75 (m, 2H)

Example 41:3-(4-Aminobutyl)-1-[(2-fluoro-4-hydroxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 41 is obtained starting from intermediate 31 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.21 (t, 1H), 6.63 (m, 1H), 6.63 (m, 1H),4.19 (dd, 2H), 3.58/3.19 (m, 2H), 3.38/3.04 (dd, 2H), 2.84 (m, 2H),2.1/1.65 (m, 2H), 1.84/1.5 (m, 2H), 1.5/1.38 (m, 2H), 1.17/1.04 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=375.1486 (375.1485)

Elemental analysis: C=51.05 (51.34); H=5.28 (6.46); N=7.76 (7.48)

Intermediate 32: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(6-oxo-1H-pyridin-3-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 32 is obtained starting from intermediate 21 and6-hydroxynicotinaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 11.45 (s, 1H), 7.35 (dd, 1H), 7.21 (df,1H), 6.31 (d, 1H), 4.1-3.9 (m, 2H), 3.4 (m, 2H), 3.32/3.19 (2*d, 2H),2.9/2.28 (2*m, 2H), 2.8/2.44 (2*dd, 2H), 2-1.7 (m, 2H), 2-1.7 (m, 2H),1.42/1.38 (2*s, 27H), 1.4 (m, 2H), 1.21 (t, 3H), 1.1-0.85 (m, 2H)

Example 42:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(6-oxo-1H-pyridin-3-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 42 is obtained starting from intermediate 32 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.74 (dd, 1H), 7.7 (d, 1H), 6.66 (d, 1H),4.17 (AB, 2H), 3.69/3.31 (2m, 2H), 3.45/3.09 (2m, 2H), 2.94 (m, 2H),2.24/1.79 (2m, 2H), 1.94/1.49 (2m, 2H), 1.61 (quint., 2H), 1.29/1.14(2m, 2H)

³¹P NMR: (300 MHz, D2O) δ ppm 25.8

ESI/FIA/HR and MS/MS: [M+H]+=358.1537 (358.1531)

Elemental analysis: C=50.77 (50.42); H=6.41 (6.77); N=11.96 (11.76)

Intermediate 33: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-(1-benzofuran-5-ylmethyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 33 is obtained starting from intermediate 21 and5-formylbenzofuran in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.98 (df, 1H), 7.55 (df, 1H), 7.53 (d,1H), 7.25 (dd, 1H), 6.91 (df, 1H), 4.1-3.9 (m, 2H), 3.72/3.51 (2*d, 2H),3.4-3.2 (m, 2H), 2.98/2.35 (2*dd, 2H), 2.81/2.48 (2*dd, 2H), 2-1.65 (m,2H), 2-1.65 (m, 2H), 1.4/1.34 (2*s, 27H), 1.39 (m, 2H), 1.21 (t, 3H),1-0.7 (m, 2H)

Example 43:3-(4-Aminobutyl)-1-(1-benzofuran-5-ylmethyl)-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 43 is obtained starting from intermediate 33 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.79 (df, 1H), 7.76 (df, 1H), 7.61 (d, 1H),7.39 (dd, 1H), 7.31/4.5 (2*d, 2H), 6.91 (df, 1H), 3.72/3.33 (2*dd, 2H),3.49/3.11 (2*dd, 2H), 2.9 (m, 2H), 2.23/1.77 (2*m, 2H), 1.91/1.57 (2*m,2H), 1.57/1.45 (2*m, 2H), 1.2/1.15 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=381.1577 (381.1579)

Elemental analysis: C=56.67 (56.84); H=6.52 (6.62); N=7.42 (7.36)

Intermediate 34: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-hydroxy-2-methylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 34 is obtained starting from intermediate 21 and4-methoxy-2-methylbenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.05 (d, 1H), 6.75 (df, 1H), 6.69 (dd,1H), 4.1-3.9 (m, 2H), 3.72 (s, 3H), 3.5/3.3 (2*d, 2H), 3.3 (m, 2H),2.9/2.41 (2*m, 2H), 2.8/2.29 (2*m, 2H), 2.3 (2*s, 3H), 2.02-1.79(unresolved peak, 2H), 2.02-1.79 (unresolved peak, 2H), 1.42/1.36 (2*s,27H), 1.32 (m, 2H), 1.21 (t, 3H), 0.68 (m, 2H)

Example 44:3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxy-2-methylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 44 is obtained starting from intermediate 34 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.25 (d, 1H), 6.81 (df, 1H), 6.77 (dd, 1H),4.29/4.22 (2*d, 2H), 3.69/3.32 (2*dd, 2H), 3.49/3.18 (2*dd, 2H), 2.94(m, 2H), 2.32 (s, 3H), 2.19/1.75 (2*m, 2H), 1.94/1.6 (2*m, 2H), 1.6/1.5(2*m, 2H), 1.27/1.12 (2*m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 26

ESI/FIA/HR and MS/MS: [M+H]+=371.1739 (371.1735)

Elemental analysis: C=54.81 (55.13); H=6.88 (7.35); N=7.52 (7.56)

Intermediate 35: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(2-chloro-4-fluorophenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 35 is obtained starting from intermediate 21 and2-chloro-4-fluorobenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.5 (dd, 1H), 7.35 (dd, 1H), 7.2 (dd,1H), 4.1-3.9 (quad., 2H), 3.65-3.55 (d, 2H), 3.4-3.3 (m, 2H), 2.9-2.35(m, 4H), 1.9 (m, 4H), 1.55-1.35 (m, 2H), 1.4-1.35 (s, 27H), 1.2 (t, 3H),0.85-0.75 (m, 2H)

³¹P NMR: (400 MHz, dmso-d6) δ ppm 45

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −112

ESI/FIA/HR and MS/MS: [M+H]+=677.3146 (677.3133)

Example 45:3-(4-Aminobutyl)-1-[(2-chloro-4-fluorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 45 is obtained starting from intermediate 35 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.56 (dd, 1H), 7.39 (dd, 1H), 7.18 (td,1H), 4.43 (sl, 2H), 3.7/3.4 (m, 2H), 3.5/3.26 (m, 2H), 2.95 (m, 2H),2.22/1.78 (m, 2H), 1.95/1.62 (m, 2H), 1.62/1.5 (m, 2H), 1.28/1.12 (m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=393.1149 (393.1146)

Elemental analysis: C=49.40 (48.93); H=5.31 (5.90); N=7.17 (7.13)

Intermediate 36: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(4-fluorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 36 is obtained starting from intermediate 21 and2-(4-fluorophenyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.5-7.2 (m, 4H), 7.5-7.2 (m, 4H),4.08-3.73 (m, 2H), 3.52/3.3 (2*d, 2H), 3.3 (m, 2H), 2.8-2.62/2.33 (2*m,2H), 2.8-2.62/2.2 (2*m, 2H), 1.98-1.63 (m, 2H), 1.98-1.63 (m, 2H),1.4/1.32 (2*s, 27H), 1.38 (m, 2H), 1.21/1.18 (2*t, 3H), 0.9-0.6 (m, 2H)

Example 46:3-(4-Aminobutyl)-1-[[2-(4-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 46 is obtained starting from intermediate 36 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (d, 1H), 7.52 (m, 2H), 7.4 (d, 1H),7.35 (dd, 2H), 7.24 (dd, 2H), 4.41/4.29 (dd, 2H), 3.39/3.1 (2*m, 2H),3.19/2.88 (2*m, 2H), 2.93 (m, 2H), 2.09/1.65 (2*m, 2H), 1.85/1.59 (2*m,2H), 1.59/1.35 (2*m, 2H), 1.2-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=435.1850 (435.1848)

Elemental analysis: C=60.73 (60.82); H=5.96 (6.50); N=6.73 (6.45)

Intermediate 37: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(2-fluorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 37 is obtained starting from intermediate 21 and2-(2-fluorophenyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (d, 1H), 7.45/7.42 (t, 2H), 7.45(m, 1H), 7.35 (m, 3H), 7.2 (d, 1H), 3.91 (m, 2H), 3.5-3.2 (m, 2H),3.5-3.2 (m, 2H), 2.67/2.29 (m, 2H), 2.67/2.13 (m, 2H), 1.95-1.6 (m, 2H),1.95-1.6 (m, 2H), 1.42 (s, 18H), 1.38 (m, 2H), 1.34 (s, 9H), 1.17 (t,3H), 0.68 (m, 2H)

Example 47:3-(4-Aminobutyl)-1-[[(2-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 47 is obtained starting from intermediate 37 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.66 (m, 1H), 7.57 (m, 1H), 7.57 (m, 1H),7.51 (m, 1H), 7.42 (m, 1H), 7.34 (m, 1H), 7.34 (m, 1H), 7.28 (t, 1H),4.6-4 (unresolved peak, 2H), 3.7-2.7 (unresolved peak, 2H), 3.7-2.7(unresolved peak, 2H), 2.93 (m, 2H), 2.14/1.69 (m, 2H), 1.87/1.37 (m,2H), 1.59 (m, 2H), 1.15/1.06 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=435.1855 (435.1848)

Elemental analysis: C=60.87 (60.82); H=6.12 (6.50); N=6.42 (6.45)

Intermediate 38: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(2,5-dichlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 38 is obtained starting from intermediate 21 and2-(2,5-dichlorophenyl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.65-7.1 (m, 7H), 4.05-3.85 (m, 2H),3.5-3.2 (m, 4H), 2.8-2.3 (m, 4H), 2.2-1.65 (m, 4H), 1.5-1.3 (m, 2H),1.45 (s, 18H), 1.35 (s, 9H), 1.2 (t, 3H), 0.8-0.5 (m, 2H)

Example 48:3-(4-Aminobutyl)-1-[[-(2,5-dichlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 48 is obtained starting from intermediate 38 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.7-7.3 (m, 7H), 4.45/4.21/4.02 (m, 2H),3.75/3.1 (2*m, 2H), 3.75/3.1 (2*m, 2H), 2.98 (m, 2H), 2.2/1.65 (2*m,2H), 1.95/1.65 (2*m, 2H), 1.65/1.15 (2*m, 2H), 1.45/1.15 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=485.1184 (485.1163)

Elemental analysis: C=54.33 (54.44); H=4.99 (5.61); N=5.86 (5.77)

Intermediate 39: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[2-(3-phenylphenyl)phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 39 is obtained starting from intermediates 21 and 241 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.7 (d, 2H), 7.65 (d, 1H), 7.6 (s, 1H),7.55 (m, 2H), 7.45 (m, 2H), 7.4-7.3 (m, 5H), 3.9 (m, 2H), 3.6/3.4 (2*d,2H), 3.4-3.2 (m, 2H), 2.85-2.65 (m, 2H), 2.35 (m, 1H), 2.2 (m, 1H), 1.9(m, 1H), 1.85-1.6 (m, 3H), 1.45-1.3 (m, 2H), 1.4/1.3 (2*s, 27H), 1.15(t, 3H), 0.65 (m, 2H)

Example 49:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-(3-phenylphenyl)phenyl]-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 49 is obtained starting from intermediate 39 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6-7.1 (m, 13H), 4.25 (d, 1H), 4.1 (d,1H), 3.4-3.2 (m, 1H), 3.15-2.9 (m, 2H), 2.75-2.55 (m, 3H), 2.05 (m, 1H),1.75 (m, 1H), 135 (m, 1H), 1.4 (m, 2H), 1.25 (m, 1H), 0.9 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=493.2256 (493.2256)

Elemental analysis: C=68.08 (68.28); H=6.02 (6.75); N=5.71 (5.69)

Intermediate 40: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[2-naphthalen-2-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 40 is obtained starting from intermediates 21 and 240 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.95 (d, 1H), 795 (m, 2H), 7.9 (s, 1H),7.55 (m, 4H), 7.4 (m, 2H), 7.3 (d, 1H), 3.9 (m, 2H), 3.65/3.45 (2*d,2H), 3.45-3.2 (m, 2H), 3.3-2.6 (m, 2H), 2.35 (dd, 1H), 2.2 (m, 1H), 1.9(m, 1H), 1.85-1.65 (m, 3H), 1.8 (m, 2H), 1.4/1.3 (2*s, 27H), 1.15 (t,3H), 0.7 (m, 2H)

Example 50:3-(4-Aminobutyl)-4-hydroxy-1-[(2-naphthalen-2-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 50 is obtained starting from intermediate 40 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.9 (d, 1H), 7.9/7.85 (2*m, 2), 7.7 (s,1H), 7.6-7.4 (m, 5H), 7.3 (m, 2H), 4.35/4.2 (2dd, 2H), 3.4-3.2 (m, 1H),3.5-2.9 (m, 2H), 2.8 (m, 2H), 2.7 (dd, 1H), 2 (m, 1H), 1.75 (m, 1H),1.65-1.35 (m, 3H), 1.25 (m, 1H), 0.85 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=467.2090 (467.2099)

Elemental analysis: C=67.58 (66.94); H=6.40 (6.70); N=5.73 (6.00)

Intermediate 41: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-{[2-(2,6-dichlorophenyl)phenyl]methyl}-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 41 is obtained starting from intermediates 21 and 242 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.65-7.5 (m, 3H), 7.5-7.3 (m, 3H), 7.1(d, 1H), 4 (m, 2H), 3.45 (m, 2H), 3.25 (2*d, 2H), 2.85-2.1 (m, 4H),2-1.75 (m, 4H), 1.6-1.15 (m, 2H), 1.45/1.4 (2*s, 27H), 1.25 (t, 3H),0.95 (m, 2H)

Example 51:3-(4-Aminobutyl)-1-[[2-(2,6-dichlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 51 is obtained starting from intermediate 41 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6 (d, 1H), 7.5/7.2 (m, 3H), 7.5-7.3 (m,2H), 7.12 (d, 1H), 3.38/3.21 (2*d, 2H), 2.82/2.38 (2*dd, 2H), 2.65/2.22(2*m, 2H), 2.45 (t, 2H), 1.85/1.71 (2*m, 2H), 1.71/1.35 (2*m, 2H),1.32/0.8 (2*m, 2H), 1.32/0.8 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=485.1169 (485.1163)

Elemental analysis: C=54.71 (54.44); H=5.14 (5.61); N=5.81 (5.77)

Intermediate 42: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-methyl-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 42 is obtained starting from intermediate 21 andformaldehyde in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 3.98 (m, 2H), 3.48 (m, 2H), 2.75 (m,2H), 2.49/2.2 (2m, 2H), 2.01 (s, 3H), 1.92 (m, 4H), 1.5 (m, 2H),1.45/1.4 (2s, 27H), 1.25/1 (2m, 2H), 1.2 (t, 3H)

Example 52:3-(4-Aminobutyl)-4-hydroxy-1-methyl-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 52 is obtained starting from intermediate 42 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 3.7-3.5 (m, 2H), 3.3 (t, 1H), 3.2 (dd, 1H),3 (t, 2H), 2.9 (s, 3H), 2.3 (n, 1H), 2 (m, 1H), 1.75 (m, 1H), 1.7 (m,2H), 1.5 (m, 1H), 1.4/1.25 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=265.1300 (265.1317)

Elemental analysis: C=45.59 (45.45); H=7.97 (8.01); N=10.61 (10.60)

Intermediate 43: tert-Butyl3-{4-[bis-(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-(2-phenylethyl)-1,4-azaphosphinane-3-carboxylate

Intermediate 43 is obtained starting from intermediate 21 andphenylacetaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.3-7.15 (m, 5H), 3.98 (m, 2H), 3.45(t, 2H), 3.05-2.3 (m, 8H), 2-1.8 (m, 4H), 1.4 (m+2s, 29H), 1.2 (t, 3H),1.18/0.9 (2m, 2H)

Example 53:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(2-phenylethyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 53 is obtained starting from intermediate 43 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.4-7.25 (m, 5H), 3.7/3.3 (2m, 2H), 3.52(m, 1H), 3.45 (t, 2H), 3.1 (m, 3H), 2.95 (m, 2H), 2.2/1.75 (2m, 2H),1.95 (m, 1H), 1.62 (m, 2H), 1.5-1.1 (m, 3H)

ESI/FIA/HR and MS/MS: [M+H]+=355.1777 (355.1786)

Elemental analysis: C=57.63 (57.62); H=7.36 (7.68); N=7.90 (7.90)

Intermediate 44: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-pentyl-1,4-azaphosphinane-3-carboxylate

Intermediate 44 is obtained starting from intermediate 21 and 1-pentanalin accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 3.98 (m, 2H), 3.8 (m, 2H), 3.49 (t,2H), 2.85 (m, 2H), 2.49/2.25 (2m, 2H), 1.9 (m, 4H), 1.45/1.4 (2s, 27H),1.45 (m, 4H), 1.25/1 (2m, 6H), 1.2 (t, 3H), 0.85 (t, 3H)

Example 54:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-pentyl-1,4-azaphosphinane-3-carboxylicAcid

Example 54 is obtained starting from intermediate 44 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 3.7-3.5 (m, 2H), 3.3 (m, 1H), 3.15/3 (2m,5H), 2.27 (m, 1H), 2 (m, 1H), 1.85-1.6 (m, 5H), 1.5/1.41 (2m, 2H), 1.3(m, 5H), 0.85 (t, 3H)

ESI/FIA/HR and MS/MS: [M+H]+=321.1923 (321.1943)

Elemental analysis: C=52.77 (52.49); H=8:93 (9.12); N=9.00 (8.74).

Intermediate 45: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino-butyl}-4-ethoxy-1-(naphthalen-1-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 45 is obtained starting, from intermediate 21 and1-naphthaldehyde in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.29 (d, 1H), 7.9/7.85 (2d, 2H),7.6-7.4 (m, 4H), 3.95 (AB, 2H), 4 (m, 2H), 3.6 (m, 2H), 3.2-2.8 (m, 4H),2.4/2 (2m, 2H), 1.7 (m, 2H), 1.4/1.3 (2s, 27H), 1.22 (t, 3H), 1.05/0.75(2m, 2H), 0.5/0.2 (2m, 2H)

Example 55:3-(4-Aminobutyl)-4-hydroxy-1-(naphthalen-1-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 55 is obtained starting from intermediate 45 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.9 (m, 3H), 7.6-7.3 (m, 4H), 4.55 (s, 2H),3.55/3.28 (2m, 2H), 3.4/3.15 (2dd, 2H), 2.75 (m, 2H), 2/1.6 (2m, 2H),1.8 (m, 1H), 1.5-1.25 (m, 3H), 1/0.9 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=391.1778 (391.1786)

Elemental analysis: C=61.34 (61.53); H=6.58 (6.97); N=7.01 (7.8)

Intermediate 46: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-(cyclohexyl-methyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 46 is obtained starting from intermediate 21 andcyclohexanal in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 4 (m, 2H), 3.5 (t, 2H), 2.8 (m, 2H),2.48/2.25 (2m, 2H), 2.15 (dd, 2H), 1.95 (m, 2H), 1.68 (m, 1H),1.65/1.4/0.8 (3m, 10H), 1.45 (m, 3H), 1.45/1.4 (2s, 27H), 1.2 (m, 2H),1.2 (t, 3H), 1 (m, 1H)

Example 56:3-(4-Aminobutyl)-1-(cyclohexylmethyl)-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 56 is obtained starting from intermediate 46 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 3.7/3.25 (2m, 2H), 3.55/3.15 (2dd, 2H),3.1-2.9 (t+2dd, 4H), 2.25 (m, 1H), 2 (m, 1H), 1.85-1.55 (m, 9H),1.52/1.41 (2m, 2H), 1.3/1.1 (m, 4H), 1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=347.2095 (347.2099)

Elemental analysis: C=55.29 (55.48); H=9.08 (9.02); N=7.95 (8.09)

Intermediate 47: tert-Butyl3-{4-bis[tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-(naphthalen-2-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 47 is obtained starting from intermediate 21 and2-naphthaldehyde in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.9 (m, 3H), 7.8 (s, 1H), 7.5 (m, 3H),3.98 (m, 2H), 3.8 (d, 1H), 3.6 (m, 3H), 3.35/3.2 (2m, 2H), 3.1-2.75 (2m,2H), 2.4 (m, 1H), 2.05-1.8 (m, 3H), 1.4-0.7 (m, 4H), 1.38 (3s, 27H),1.22 (t, 3H)

Example 57:3-(4-Aminobutyl)-4-hydroxy-1-(naphthalen-2-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 57 is obtained starting from intermediate 47 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.95-7.9 (m, 4H), 7.6-7.5 (m, 3H), 4.5;4.3(d, 2*1H H), 3.65 (m, 1H), 3.45-3.3 (m, 2H), 3.15 (m, 1H), 2.8 (m, 2H),2.25 (m, 1H), 1.9-1.7 (m, 2H), 1.55-1.4 (m, 3H), 1.15-0.95 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=391.1778 (391.1786)

Elemental analysis: C=61.31 (61.53); H=6.56 (6.97); N=7.15 (7.18)

Intermediate 48: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(4-chlorophenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 48 is obtained starting from intermediate 21 and4-chlorobenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.4 (d, 2H), 7.31 (d, 2H), 3.98 (m,2H), 3.65-3.3 (m, 4H), 3-2.3 (m, 4H), 2-1.8 (m, 4H), 1.4 (s+m, 29H),1.22 (2t, 3H), 0.8 (m, 2H)

Example 58:3-(4-Aminobutyl)-1-[(4-chlorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 58 is obtained starting from intermediate 48 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5/7.45 (2d, 4H), 4.41/4.21 (2d, 2H),3.7/3.33 (2m, 2H), 3.45/3.1 (2dd, 2H), 2.95 (m, 2H), 2.25/1.78 (2m, 2H),1.95/1.5 (2m, 2H), 1.6 (m, 2H), 1.25/1.1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=375.1242 (375.1240)

Elemental analysis: C=50.89 (51.27); H=6.01 (6.45); N=7.44 (7.47)

Intermediate 49: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-fluorophenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 49 is obtained starting from intermediate 21 and4-fluorobenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.35 (m, 2H), 7.15 (t, 2H), 4 (m, 2H),3.65-3.3 (m, 4H), 3-2.3 (m, 4H), 2-1.8 (m, 4H), 1.4 (s+m, 29H), 1.2 (2t,3H), 0.9/0.8 (2m, 2H)

Example 59:3-(4-Aminobutyl)-1-[(4-fluorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 59 is obtained starting from intermediate 49 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5 (dd, 2H), 7.2 (t, 2H), 4.41/4.21 (2d,2H), 3.7/3.31 (2m, 2H), 3.45/3.1 (2dd, 2H), 2.95 (m, 2H), 2.25/1.78 (2m,2H), 1.95/1.5 (2m, 2H), 1.6 (m, 2H), 1.25/1.1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=359.1532 (359.1535)

Elemental analysis: C=53.65 (53.63); H=6.20 (6.75); N=7.83 (7.82)

Intermediate 50: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-(furan-2-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 50 is obtained starting from intermediate 21 and2-furaldehyde in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, CDCl3) δ ppm 7.41 (s, 1H), 6.32 (s, 1H), 6.2 (s, 1H),4.09 (s, 2H), 3.62/3.52 (AB, 2H), 3.5 (m, 2H), 3/2.65 (m, 2H), 2.96/2.52(m, 2H), 2.7-1.8 (m, 4H), 1.5/1.46 (m, 30H), 1.3 (t, 3H), 1.01 (m, 1H)

³¹P NMR: (400 MHz, CDCl3) δ ppm 46.14

Example 60:3-(4-Aminobutyl)-1-(furan-2-ylmethyl)-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 60 is obtained starting from intermediate 50 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7:6 (sl, 1H), 6.7 (tf, 1H), 6.5 (tf, 1H),4.45/4.32 (2d, 2H), 3.7/3.3 (2*m, 2H), 3.52/3.12 (2*m, 2H), 2.98 (m,2H), 2.25/1.8. (2*m, 2H), 1.95/1.5 (2*m, 2H), 1.62 (m, 2H), 1.32/1.2(2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=331.142 (331.1422)

Elemental analysis: C=50.48 (50.91); H=6.48 (7.02); N=8.37 (8.48)

Intermediate 51: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 51 is obtained starting from intermediate 21 and4-trifluoromethylbenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.71 (d, 2H), 7.52 (d, 2H), 4.03 (m,2H), 3.72/3.51 (2*d, 2H), 3.35 (m, 2H), 3-2.3 (m, 4H), 1.98 (m, 4H), 1.4(s+m, 29H), 1.2 (t, 3H), 0.8 (m, 2H)

Example 61:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[4-(trifluoromethyl)phenyl]-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 61 is obtained starting from intermediate 41 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.8 (d, 2H), 7.65 (d, 2H), 4.5/4.3 (AB,2H), 3.7/3.45 (m, 2H), 3.39/3.11 (m, 2H), 2.9 (m, 2H), 2.28/1.8 (m, 2H),1.95/1.49 (m, 2H), 1.6 (m, 2H), 1.2/1.1 (m, 2H)

¹⁹F NMR: (400 MHz, D2O) δ ppm −62.5

³¹P NMR: (400 MHz, D2O) δ ppm 24

ESI/FIA/HR and MS/MS: [M+H]+=409.1510 (409.1504)

Elemental analysis: C=49.86 (50.00); H=5.32 (5.92); N=6.83 (6.86)

Intermediate 52: tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-methoxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 52 is obtained starting from intermediate 21 and4-methoxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.2 (d, 2H), 6.9 (d, 2H), 3.98 (m, 2H),3.72 (s, 3H), 3.6/3.32 (2*d, 2H), 3.4 (m, 2H), 3-2.25 (m, 4H), 1.9 (m,4H), 1.4 (s+m, 29H), 1.2 (t, 3H), 0.8 (m, 2H)

Example 62:3-(4-Aminobutyl)-4-hydroxy-1-[(4-methoxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 62 is obtained starting from intermediate 52 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.41 (d, 2H), 7.02 (d, 2H), centred at 4.25(AB, 2H), 3.8 (s, 3H), 3.7/3.3 (2m, 2H), 3.45/3.08 (2dd, 2H), 2.95 (m,2H), 2.25/1.75 (2m, 2H), 1.95/1.45 (2m, 2H), 1.6 (m, 2H), 1.25/1.1 (2m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=371.1712 (371.1730)

Elemental analysis: C=54.93 (55.13); H=7.41 (7.35); N=7.56 (7.56)

Intermediate 53: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-(thiophen-3-ylmethyl)-1,4-azaphosphinane-3-carboxylate

Intermediate 53 is obtained starting from intermediate 21 and3-thiophenaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (m, 1H), 7.31 (m, 1H), 7.02 (m,1H), 3.95 (m, 2H), 3.6/3.49 (AB, 2H), 3.4 (m, 2H), 3/2.8 (m, 2H),2.8/2.45 (m, 2H), 1.9 (m, 4H), 1.4 (m, 29H), 1.2 (t, 3H), 0.95/0.85 (m,2H)

³¹P NMR: (400 MHz, dmso-d6) δ ppm 47/45

Example 63:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(thiophen-3-ylmethyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 63 is obtained starting from intermediate 53 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.61 (d, 1H), 7.54 (dd, 1H), 7.2 (d, 1H),4.42/4.28 (2*d, 2H), 3.71/3.32 (m, 2H), 3.48/3.06 (m, 2H), 2.94 (m, 2H),2.25/1.77 (m, 2H), 193/1.46 (m, 2H), 1.6 (m, 2H), 1.26/1.13 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=347.1182 (347.1189)

Elemental analysis: C=48.14 (48.55); H=6.55 (6.69); N=7.87 (8.09);S=8.65 (9.26)

Intermediate 54: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-hydroxy-3-methoxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 54 is obtained starting from intermediate 21 and4-hydroxy-3-methoxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.8 (s, 1H), 6.8 (df, 1H), 6.7 (d, 1H),6.62 (dd, 1H), 3.95 (m, 2H), 3.71 (s, 3H), 3.49/3.31 (2d, 2H), 3.4 (m,2H), 3-2.2 (m, 4H), 2-1.8 (m, 4H), 1.4 (2s+m, 29H), 1.2 (2t, 3H), 1/0.85(2m, 2H)

Example 64:3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxy-3-methoxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 64 is obtained starting from intermediate 54 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.09 (m, 1H), 6.94 (m, 2H), 4.3/4.13 (2*d,2H), 3.7/3.3 (2*m, 2H), 3.65 (s, 3H), 3.45/3.07 (2*m, 2H), 2.92 (m, 2H),2.22/1.77 (2*m, 2H), 1.92/1.6 (2*m, 2H), 1.6/1.48 (2*m, 2H), 1.23/1.11(2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=387.1665 (387.1685)

Elemental analysis: C=53.10 (52.85); H=7.01 (7.04); N=7.30 (7.25)

Intermediate 55: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(2-carboxyphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 55 is obtained starting from intermediate 21 and methyl2-formylbenzoate in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.65 (d, 1H), 7.5 (t, 1H), 7.38 (m,2H), 4.05/3.4 (2d, 2H), 3.95 (m, 2H), 3.8 (2s, 3H), 3.3/3.2 (2m, 2H),3-2.35 (m, 4H), 2 (m, 1H), 1.8-1.6 (m, 3H), 1.4/1.3 (2s+m, 29H), 1.2(2t, 3H), 0.5/0.35 (2m, 2H)

Example 65:3-(4-Aminobutyl)-1-[(2-carboxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 55 is obtained starting from intermediate 65 in accordance withprocedure D described hereinbefore.

ESI/FIA/HR and MS/MS [M+H]+=385.1504 (385.1523)

Elemental analysis: C=53.42 (53.12); H=6.25 (6.56); N=7.40 (7.29)

Intermediate 56: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(3-chloro-4-hydroxyphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 56 is obtained starting from intermediate 21 and3-chloro-4-hydroxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.05 (m, 1H), 7.22 (df, 1H), 7.02 (dd,1H), 6.9 (d, 1H), 3.98 (m, 2H), 3.5/3.31 (2d, 2H), 3.4 (m, 2H), 3-2.25(m, 4H), 2-1.8 (m, 4H), 1.4 (2s+m, 29H), 1.2 (2t, 3H), 1.1-0.8 (2m, 2H)

Example 66:3-(4-Aminobutyl)-1-[(3-chloro-4-hydroxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 66 is obtained starting from intermediate 56 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.42 (df, 1H), 7.2 (dd, 1H), 6.97 (d, 1H),4.27/4.07 (2*d, 2H), 3.62/3.22 (2*m, 2H), 3.39/3 (2*m, 2H), 2.85 (m,2H), 2.18/1.7 (2*m, 2H), 1.85/1.52 (2*m, 2H), 1.52/1.4 (2*m, 2H),1.18/1.05 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=391.1189 (391.1189)

Elemental analysis: C=49.09 (49.17); H=6.02 (6.19); N=7.18 (7.17)

Intermediate 57: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-hydroxy-3-(trifluoromethoxy)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 57 is obtained starting from intermediate 21 and4-hydroxy-3-(trifluoromethyl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 10.1 (m, 1H), 7.15 (df, 1H), 7.08 (dd,1H), 6.95 (d, 1H), 3.98 (m, 2H), 3.5/3.4 (2d, 2H), 3.4 (m, 2H), 3-2.2(m, 4H), 2-1.8 (m, 4H), 1.4 (2s+m, 29H), 1.2 (2t, 3H), 1.1-0.8 (2m, 2H)

Example 67:3-(4-Aminobutyl)-4-hydroxy-1-[[4-hydroxy-3-(trifluoromethoxy)-phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 67 is obtained starting from intermediate 57 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.44 (df, 1H), 7.33 (dd, 1H), 7.09 (d, 1H),4.38/4.13 (2*d, 2H), 3.7/3.31 (2*dd, 2H), 3.44/3.07 (2*dd, 2H), 2.92 (m,2H), 2.23/1.78 (2*m, 2H), 1.94/1.59 (2*m, 2H), 1.59/1.46 (2*m, 2H),1.21/1.1 (2*m, 2H)

¹⁹F NMR: (400 MHz, D2O) δ ppm −58.3

³¹P NMR: (400 MHz, D2O) δ ppm 26

ESI/FIA/HR and MS/MS: [M+H]+=441.1403 (441.1402)

Elemental analysis: C=46.46 (46.37); H=4.98 (5.49); N=6.42 (6.36)

Intermediate 58: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-hydroxy-3,5-dimethylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 58 is obtained starting from intermediate 21 and3,5-dimethyl-4-hydroxybenzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.09 (s, 1H), 6.8 (s, 2H), 3.98 (m,2H), 3.49/3.21 (2d, 2H), 3.35 (m, 2H), 3-2.2 (m, 4H), 2.15 (s, 6H),2-1.8 (m, 4H), 1.4 (2s+m, 29H), 1.2 (2t, 3H), 0.95-0.82 (2m, 2H)

Example 68:3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxy-3,5-dimethylphenyl)-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 68 is obtained starting from intermediate 58 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.1 (s, 2H), 4.25-4.1 (d, 2H), 3.7-3.5 (m,2H), 3.25 (m, 1H), 3.1 (m, 1H), 2.95 (t, 2H), 2.2 (s, 6H), 2.2/1.75 (m,2H), 1.95 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 1.3-1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=385.1889 (385.1892)

Elemental analysis: C=55.50 (56.24); H=7.07 (7.60); N=7.16 (7.29)

Intermediate 59: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-(pyridin-4-ylmethyl)-1,4-azaphosphinane-3-carboxylate

Intermediate 59 is obtained starting from intermediate 21 and4-formylpyridine in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.5 (d, 2H), 7.3 (d, 2H), 4.1-3.9 (2m,2H), 3.65/3.52 (2×2d, 2H), 3.45 (2m, 2H), 2.95-2.3 (m, 4H), 1.98 (m,4H), 1.5-1.35 (m+s, 29H), 1.22 (2t, 3H), 1.05 (m, 2H)

Example 69:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(pyridin-4-ylmethyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 69 is obtained starting from intermediate 59 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.5 (d, 2H), 8.05 (m, 3H), 7.3 (d, 2H),3.55 (AB, 2H), 3.05/2.3 (2m, 2H), 2.7 (m, 3H), 2.5 (m, 1H), 1.75 (m,1H), 1.65-1.15 (m, 7H)

ESI/FIA/HR and MS/MS: [M+H]+=342.1577 (342.1582)

Elemental analysis: C=52.56 (52.78); H=6.70 (7.09); N=12.22 (12.31)

Intermediate 60: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-(pyridin-3-ylmethyl)-1,4-azaphosphinane-3-carboxylate

Intermediate 60 is obtained starting from intermediate 21 and3-formylpyridine in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.5 (d+s, 2H), 7.7 (2dd, 1H), 7.35 (m,1H), 4.1-3.9 (2m, 2H), 3.65/3.52 (2×2d, 2H), 3.45 (2m, 2H), 3-2.3 (at,4H), 1.9 (m, 4H), 1.4 (m+s, 30H), 1.22 (2t, 3H), 0.82 (m, 1H)

Example 70:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(pyridin-3-ylmethyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 70 is obtained starting from intermediate 60 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.6 (s+d, 2H), 8 (dd, 1H), 7.52 (dd, 1H),4.4 (AB, 2H), 3.7 (m, 1H), 3.4 (m, 2H), 3.18 (dd, 1H), 2.9 (m, 2H),2.28/1.8 (2m, 2H), 1.91 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 1.21/1.1 (2m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=342.1568 (342.1582)

Elemental analysis: C=52.32 (52.78); H=6.66 (7.09); N=12.32 (12.31)

Intermediate 61: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-(pyridin-2-ylmethyl)-1,4-azaphosphinane-3-carboxylate

Intermediate 61 is obtained starting from intermediate 21 and2-formylpyridine in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.5 (df, 1H), 7.75 (t, 1H), 7.42/7.25(2dd, 2H), 4.1-3.9 (2m, 2H), 3.71/3.6 (2AB, 2H), 3.5-3.35 (m, 2H), 3-2.3(m, 4H), 2.0-2.9 (m, 4H), 1.45/1.35 (3s, 27H), 1.4/1-0.8 (3m, 4H), 1.22(2t, 3H)

Example 71:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(pyridin-2-ylmethyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 71 is obtained starting from intermediate 61 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.6 (dd, 1H), 7.91 (t, 1H), 7.55 (d, 1H),7.45 (dd, 1H), centred at 4.41 (AB, 2H), 3.75/3.4 (2m, 2H), 3.55/3.3(2dd, 2H), 2.95 (m, 2H), 2.3/1.78 (2m, 2H), 1.98 (m, 1H), 1.65 (m, 2H),1.5 (m, 1H), 1.3/1.2 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=342.1592 (342.1582)

Elemental analysis: C=52.72 (52.78); H=6.92 (7.09); N=12.25 (12.31)

Intermediate 63: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-(2-cyclohexylethyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 63 is obtained starting from intermediate 21 and2-cyclohexylacetaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 3.98 (m, 2H), 3.48 (t, 2H), 2.8 (m,2H), 2.5-2.2 (m, 4H), 2-0.8 (m, 19H), 1.9 (m, 2H), 1.45/1.4 (2s, 27H),1.2 (t, 3H)

Example 73:3-(4-Aminobutyl)-1-(2-cyclohexylethyl)-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 73 is obtained starting from intermediate 63 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 3.7-3.5 (m, 2H), 3.3 (m, 1H), 3.15 (m, 3H),3 (t, 2H), 2.22/1.8 (2m, 2H), 2 (m, 1H), 1.7-0.85 (m, 17H), 1.65 (m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=361.2257 (361.2256)

Elemental analysis: C=56.25 (56.65); H=8.92 (9.23); N=7.49 (7.77)

Intermediate 64: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(4-phenylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 64 is obtained starting from intermediate 21 and4-phenylbenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.69 (2d, 4H), 7.5-7.3 (m, 5H), 4 (m,2H), 3.7/3.45 (2d, 2H), 3.4 (m, 2H), 3.05-2.3 (m, 4H), 2.05-1.65 (m,4H), 1.4 (m+2s, 29H), 1.22 (2t, 3H), 1-0.7 (m, 2H)

Example 74:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(4-phenylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 74 is obtained starting from intermediate 64 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.8 (d, 2H), 7.7 (d, 2H), 7.55 (d, 2H), 7.5(t, 2H), 7.41 (t, 1H), 4.45/4.28 (2d, 2H), 3.75/3.35 (2m, 2H), 3.5/3.15(2dd, 2H), 2.9 (m, 2H), 2.25/1.8 (2m, 2H), 1.95/1.45 (2m, 2H), 1.6 (m,2H), 1.25/1.1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=417.1932 (417.1943)

Elemental analysis: C=63.25 (63.45); H=6.64 (7.02); N=6.55 (6.73)

Intermediate 65: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(3-phenoxyphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 65 is obtained starting from intermediate 21 and3-phenoxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.38 (2t, 3H), 7.15 (t, 1H), 7.05 (d,1H), 7.05 (d, 2H), 6.95 (sl, 1H), 6.9 (d, 1H), 3.98 (m, 2H), 3.6/3.45(2d, 2H), 3.4 (m, 2H), 3-2.3 (m, 4H), 2-1.6 (m, 6H), 1.4 (2s, 27H), 1.2(2t, 3H), 1-0.75 (m, 2H)

Example 75:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(3-phenoxyphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 75 is obtained starting from intermediate 65 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5-7.3 (2t, 3H), 7.2-6.95 (m, 6H), centredat 4.2 (AB, 2H), 3.65/3.25 (2m, 2H), 3.4/3 (2dd, 2H), 2.82 (m, 2H),2.19/1.7 (2m, 2H), 1.88/1.4 (2m, 2H), 1.52 (m, 2H), 1.2-1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=433.1891 (433.1892)

Elemental analysis: C=60.90 (61.10); H=6.58 (6.76); N=6.34 (6.48)

Intermediate 66: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-(3-phenylpropyl)-1,4-azaphosphinane-3-carboxylate

Intermediate 66 is obtained starting from intermediate 21 and3-phenylpropanal in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.29 (t, 2H), 7.15 (d+t, 3H), 3.98 (m,2H), 3.49 (t, 2H), 2.9-2.2 (m, 4H), 2.59 (t, 2H), 2.35 (m, 2H), 2-1.6(m, 7H), 1.5 (m, 1H), 1.4 (2s, 27H), 1.25/1 (2m, 2H), 1.2 (2t, 3H)

Example 76:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(3-phenylpropyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 76 is obtained starting from intermediate 66 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.38 (t, 2H), 7.27 (m, 3H), 3.62/328 (2m,2H), 3.52 (dd, 1H), 3.11 (m, 3H), 3 (td, 2H), 2.7 (t, 2H), 2.25/1.75(2m, 2H), 2.09 (m, 2H), 1.95/1.5 (2m, 2H), 1.65 (m, 2H), 1.38/1.22 (2m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=369.195 (369.1943)

Elemental analysis: C=58.46 (58.68); H=7.45 (7.93); N=7.54 (7.60)

Intermediate 68: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(4-phenoxyphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 68 is obtained starting from intermediate 21 and4-phenoxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.4 (t, 2H), 7.3 (d, 2H), 7.12 (t, 1H),6.98 (2d, 4H), 3.99 (m, 2H), 3.6/3.4 (2d, 2H), 3.38 (m, 2H), 3-2.25 (m,4H), 2-1.65 (m, 6H), 1.4 (2s, 27H), 1.2 (2t, 3H), 1-0.75 (m, 2H)

Example 78:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(4-phenoxyphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 78 is obtained starting from intermediate 68 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.44 (d, 2H), 7.41 (t, 2H), 7.21 (t, 1H),7.08 (d, 2H), 7.08 (d, 2H), 4.38/4.21 (2d, 1+1H), 3.7/3.31 (m+m, 1+1H),3.5/3.1 (2d, 2H), 2.93 (m, 2H), 2.23/1.77 (m+m, 1+1H), 1.93/1.48 (m+m,1+1H), 1.6 (quint., 2H), 1.24/1.13 (m+m, 1+1H)

¹³C NMR: (400 MHz, D2O) δ ppm 177.6, 158.2, 155.7, 132.1, 130, 124.3,124.1, 119.3, 118.7, 59.4, 51.6, 50.9, 38.8, 27, 26.6, 24.8, 20

³¹P NMR: (400 MHz, D2O) δ ppm 25

ESI/FIA/HR and MS/MS: [M+H]+=433.1884 (433.1892)

Elemental analysis: C=60.77 (61.10); H=6.27 (6.76); N=6.42 (6.48)

Example 79:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(2-phenylmethoxyethyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 79 is obtained starting from intermediate 21 andbenzyloxyacetaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.42 (m, 5H), 4.63 (d, 1H), 4.55 (d, 1H),3.82 (t, 2H), 3.61 (dd, 1H), 3.5 (m, 1H), 3.33 (m, 2H), 3.26 (m, 1H),3.16 (dd, 1H), 2.92 (t, 2H), 2.24 (m, 1H), 1.94 (m, 1H), 1.71 (m, 1H),1.61 (quint, 2H), 1.48 (m, 1H), 1.21 (m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 25.6

ESI/FIA/HR and MS/MS: [M+H]+=385.1883 (385.1892)

Example 80:3-(4-Aminobutyl)-4-hydroxy-1-(2-hydroxyethyl)-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 80 is obtained starting from Example 79 in accordance withprocedure E described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 3.9 (m, 2H), 3.72 (dd, 1H), 3.62 (dd, 1H),3.32 (m, 1H), 3.29 (t, 2H), 3.25 (dd, 1H), 2.99 (m, 2H), 2.29 (m, 1H),1.99 (m, 1H), 1.79 (m, 1H), 1.67 (quint, 2H), 1.52 (m, 1H), 1.41 (m,1H), 1.29 (m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=295.1424 (295.1422)

Elemental analysis: C=44.08 (44.90); H=7.66 (7.88); N=9.23 (9.52)

Intermediate 69: tert-Butyl3-{4-[Bis(tert-butoxycarbonyl)amino]butyl}-1-[(3-chlorophenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 69 is obtained starting from intermediate 21 and3-chlorobenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.4-7.2 (m, 4H), 3.99 (m, 2H),3.62/3.43 (AB, 1+1H), 3.38 (m, 2H), 2.92/2.36 (m)+(m, 1+1H), 2.73/2.47(m)+(m, 1+1H), 1.96 (m, 2H), 1.89 (m, 2H), 1.41 (m, 2H), 1.37/1.33(2*(s, 27H), 1.2 (t, 3H), 0.81 (m, 2H)

¹³C NMR: (400 MHz, dmso-d6) δ ppm 127-130, 152.3, 60.9, 60.6, 54.9,51.6, 45.6, 28.9, 28.9, 27.6, 24.7, 20.6, 133.2, 81.8/81.1

Example 81:3-(4-Aminobutyl)-1-[(3-chlorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 81 is obtained starting from intermediate 69 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.52-7.35 (m, 4H), centred at 4.32 (AB,2H), 3.7/3.32 (2m, 2H), 3.5/3.12 (2dd, 2H), 2.93 (m, 2H), 2.25/1.8 (2m,2H), 1.95/1.48 (2m, 2H), 1.6 (m, 2H), 1.25/1.11 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=375.1256 (375.1240)

Elemental analysis: C=51.26 (51.27); H=6.32 (6.45); N=7.43 (7.47)

Intermediate 70: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(3-hydroxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 70 is obtained starting from intermediate 21 and3-hydroxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.25 (s, 1H), 7.1 (t, 1H), 6.7-6.55 (m,3H), 3.98 (m, 2H), 3.52/3.4 (2d, 2H), 3.4 (m, 2H), 3-2.2 (m, 4H), 2-1.65(m, 6H), 1.4 (2s, 27H), 1.2 (2t, 3H), 0.95/0.82 (2m, 2H)

Example 82:3-(4-Aminobutyl)-4-hydroxy-1-[(3-hydroxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 82 is obtained starting from intermediate 70 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.38 (t, 1H), 7-6.9 (m, 3H), centred at4.18 (AB, 2H), 3.7/3.32 (2m, 2H), 3.45/3.1 (2dd, 2H), 2.91 (m, 2H),2.25/1.8 (2m, 2H), 1.92/1.48 (2m, 2H), 1.6 (m, 2H), 1.25/1.1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=357.1573 (357.1579)

Elemental analysis: C=53.22 (53.93); H=6.98 (7.07); N=7.72 (7.86)

Intermediate 71: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-hydroxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 71 is obtained starting from intermediate 21 and4-hydroxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.25 (s, 1H), 7.05 (d, 2H), 6.7 (d,2H), 3.98 (m, 2H), 3.49/3.3 (2d, 2H), 3.4 (m, 2H), 3-2.2 (m, 4H), 2-1.8(m, 4H), 1.4 (2s+m, 29H), 1.2 (2t, 3H), 0.95/0.82 (2m, 2H)

Example 83:3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 83 is obtained starting from intermediate 71 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.38 (d, 2H), 6.95 (d, 2H), centred at 4.25(AB, 2H), 3.7/3.3 (2m, 2H), 3.48/3.05 (2dd, 2H), 2.95 (m, 2H), 2:21/1.75(2m, 2H), 1.95/1.5 (2m, 2H), 1.6 (m, 2H), 1.25/1.11 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=357.1572 (357.1579)

Elemental analysis: C=53.24 (53.93); H=6.89 (7.07); N=7.57 (7.86)

Intermediate 72: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-(furan-3-ylmethyl)-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 72 is obtained starting from intermediate 21 and3-furaldehyde in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.61/7.55 (2sl, 2H), 6.39 (sl, 1H),3.98 (m, 2H), 3.49/3.33 (2d, 2H), 3.45 (m, 2H), 3-2.2 (m, 4H), 2-1.8 (m,4H), 1.4 (2s+m, 29H), 1.2 (2t, 3H), 1.05/0.9 (2m, 2H)

Example 84:3-(4-Aminobutyl)-1-(furan-3-ylmethyl)-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 84 is obtained starting from intermediate 72 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.71 (sl, 1H), 7.59 (sl, 1H), 6.58 (sl,1H), centred at 4.22 (AB, 2H), 3.7/3.35 (2m, 2H), 3.55/3.08 (2dd, 2H),2.95 (m, 2H), 2.25/1.8 (2m, 2H), 1.95/1.5 (2m, 2H), 1.62 (m, 2H),1.31/1.18 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=331.1431 (331.1422)

Elemental analysis: C=50.45 (50.91); H=6.72 (7.02); N=8.39 (8.48)

Intermediate 73: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(2-hydroxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 73 is obtained starting from intermediate 21 and2-hydroxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.45 (s, 1H), 7.1 (d+t, 2H), 6.78 (d+t,2H), 4 (m, 2H), 3.62/3.52 (2d, 2H), 3.4 (m, 2H), 3-2.3 (m, 4H), 2-1.8(m, 4H), 1.42/1.38 (m+2s, 29H), 1.21 (2t, 3H), 0.98/0.85 (2m, 2H)

Example 85:3-(4-Aminobutyl)-4-hydroxy-1-[(2-hydroxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 85 is obtained starting from intermediate 73 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.39 (t, 1H), 7.3 (d, 1H), 6.95 (d+t, 2H),4.28 (AB, 2H), 3.65/3.28 (2m, 2H), 3.52/3.2 (2dd, 2H), 2.95 (m, 2H),2.2/1.72 (2m, 2H), 1.98/1.5 (2m, 2H), 1.62 (m, 2H), 1.3/1.18 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=357.1591 (357.1579)

Elemental analysis: C=53.22 (53.93); H=6.97 (7.07); N=7.71 (7.86)

Intermediate 74: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(4-hydroxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 74 is obtained starting from intermediate 21 and2-(4-hydroxyphenyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.45 (s, 1H), 7.45 (dd, 1H), 7.3 (td,2H), 7.16 (dd, 1H), 7.13 (d, 2H), 6.81 (d, 2H), 3.93 (quad., 2H),3.54/3.36 (d, 2H), 3.28 (t, 2H), 2.85-2.15 (m, 2H), 2.85-2.15 (m, 2H),1.84 (m, 2H), 1.84 (m, 2H), 1.47-1.3 (s, 27H), 1.47-1.3 (s, 2H), 1.17(t, 3H), 0.7 (m, 2H)

³¹P NMR: (400 MHz, dmso-d6) δ ppm 45.3

Example 86:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(4-hydroxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 86 is obtained starting from intermediate 74 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.56 (dd, 1H), 7.55-7.45 (2td, 2H), 7.37(dd, 1H), 7.25 (d, 2H), 7 (d, 2H), 4.36 (dd, 2H), 3.35/3.1 (2m, 2H),3.2/2.85 (2m, 2H), 2.95 (m, 2H), 2.05/1.65 (2m, 2H), 1.85/1.35 (2m, 2H),1.6 (m, 2H), 1.2-0.95 (m, 2H),

ESI/FIA/HR and MS/MS: [M+H]+=433.1893 (433.1892)

Elemental analysis: C=61.11 (61.10); H=6.10 (6.76); N=6.68 (6.48)

Intermediate 75: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(3-phenyl-1H-pyrazol-4-ylmethyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 75 is obtained starting from intermediate 21 and3-phenyl-1H-pyrazole-4-carboxaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13-12.5 (m, 1H), 7.9-7.3 (m, 6H),4.05-3.9 (m, 2H), 3.45 (dd, 2H), 3.3 (m, 2H), 3.1-2.2 (m, 6H), 2-1.7 (m,2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.2 (m, 2H), 1.2 (t, 3H), 1-0.7 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=691.3829 (691.3835)

Example 87:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(3-phenyl-1H-pyrazol-4-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 87 is obtained starting from intermediate 75 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.95 (sl, 1H), 7.6-7.5 (m, 5H), 4.45 (dd,2H), 3.55/3.15 (2m, 2H), 3.05/2.7 (2m, 2H), 2.9 (m, 2H), 2.2/1.7 (m,2H), 1.8/1.25 (2m, 2H), 1.5 (m, 2H), 0.95/0.7 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=407.1865 (407.1848)

Elemental analysis: C=55.99 (56.15); H=6.40 (6.70); N=13.79 (13.79)

Intermediate 76: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(4-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 76 is obtained starting from intermediate 21 and2-(4-methoxyphenyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.47 (d, 1H), 7.32 (m, 2H), 7.27 (d,2H), 7.19 (d, 1H), 7 (d, 2H), 3.93 (m, 2H), 3.8 (s, 3H), 3.54/3.37 (2*d,2H), 3.32 (m, 2H), 2.74/2.22 (m, 2H), 2.74/2.33 (m, 2H), 1.95-1.75 (m,2H), 1.95-1.75 (m, 2H), 1.41 (s, 18H), 1.37 (m, 2H), 1.34 (s, 9H), 1.18(t, 3H), 0.7 (m, 2H)

Example 88:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(4-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 88 is obtained starting from intermediate 76 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.59 (dd, 1H), 7.51 (m, 2H), 7.38 (dd, 1H),7.31 (d, 2H), 7.1 (d, 2H), 4.44/4.29 (2*d, 2H), 3.36 (s, 3H), 3.19/2.94(m, 2H), 3.19/2.84 (m, 2H), 2.94 (m, 2H), 2.08/1.65 (m, 2H), 1.85/1.35(m, 2H), 1.58 (m, 2H), 1.13/1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=447.2046 (447.2048)

Elemental analysis: C=62.04 (61.87); H=6.38 (7.00); N=6.05 (6.27)

Intermediate 77: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(4-phenyl-1H-pyrazol-3-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 77 is obtained starting from intermediate 21 and4-phenyl-1H-pyrazole-3-carboxaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13-12.5 (m, 1H), 8 (m, 1H), 7.62 (d,2H), 7.35 (t, 2H), 7.2 (t, 1H), 4.1-3.9 (m, 2H), 3.8-3.35 (m, 2H), 3.25(m, 2H), 3.15-2.3 (m, 4H), 2.1-1.9 (m, 2H), 1.8 (m, 2H), 1.4-1.2 (m,2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.2 (t, 3H), 0.7 (m, 2H)

Example 89:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(4-phenyl-1H-pyrazol-3-ylmethyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 89 is obtained starting from intermediate 77 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.9 (s, 1H), 7.55-7.35 (m, 5H), 4.65-4.4(dd, 2H), 3.55/3.15 (2m, 2H), 3.15/2.9 (2m, 2H), 2.9 (m, 2H), 2.15/1.65(2m, 2H), 1.8/1.25 (m, 2H), 1.5 (m, 2H), 0.95/0.75 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=407.1844 (407.1848)

Elemental analysis: C=56.58 (56.15); H=6.24 (6.70); N=13.79 (13.79)

Intermediate 78: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(5-phenyl-1,3-oxazol-4-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 78 is obtained starting from intermediate 21 and5-phenyl-1,3-oxazole-4-carboxaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 8.29 (s, 1H), 7.78 (m, 2H), 7.5 (m,2H), 7.4 (m, 1H), 4 (m, 2H), 3.68 (dd, 2H), 3.3 (m, 2H), 3.05/2.5 (2m,2H), 2.95/2.65 (2m, 2H), 2.05-1.7 (m, 4H), 1.45 (s, 18H), 1.35 (s, 9H),1.25 (m, 2H), 1.25 (t, 3H), 0.9 (m, 2H)

Example 90:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(5-phenyl-1,3-oxazol-4-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 90 is obtained starting from intermediate 78 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.28 (s, 1H), 7.68 (d, 2H), 7.6-7.5 (m,3H), 4.55 (dd, 2H), 3.65/3.3 (2m, 2H), 3.4/3.1 (2dd, 2H), 2.9 (m, 2H),2.2/1:71 (2m, 2H), 1.9/1.35 (2m, 2H), 1.55 (m, 2H), 1.05/0.95 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=408.1689 (408.1688)

Elemental analysis: C=55.52 (56.02); H=6.16 (6.43); N=10.20 (10.31)

Intermediate 79: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(1,2-oxazol-5-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 79 is obtained starting from intermediates 21 and 218 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 8.6 (d, 1H), 7.65 (m, 1H), 7.55-7.4 (m,3H), 6.75 (d, 1H), 4 (m, 2H), 3.85/3.5 (dd, 2H), 3.3 (m, 2H), 2.95/2.4(2m, 2H), 2.8/2.55 (2m, 2H), 2.1-1.6 (2m, 4H), 1.45 (s, 18H), 1.35 (m,2H), 1.35 (s, 9H), 1.22 (t, 3H), 0.9-0.5 (m, 2H)

Example 91:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(1,2-oxazol-5-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 91 is obtained starting from intermediate 79 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.55 (d, 1H), 7.85 (m, 1H), 7.65-7.55 (m,3H), 6.85 (d, 1H), 4.7/4.4 (dd, 2H), 3.85/3.2 (2m, 2H), 3.5/3.2 (2dd,2H), 2.9 (m, 2H), 2.3/1.8 (2m, 2H), 1.9/1.45 (2m, 2H), 1.6 (m, 2H),1.2/1.05 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=408.1685 (408.1688)

Elemental analysis: C=55.14 (56.02); H=5.95 (6.43); N=10.14 (10.31)

Intermediate 80: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-pyrazol-1-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 80 is obtained starting from intermediate 21 and2-(1H-pyrazol-1-yl)-benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.04 (d, 1H), 7.7 (d, 1H), 7.55-7.35(m, 4H), 6.5 (m, 1H), 3.95 (m, 2H), 3.65/3.35 (dd, 2H), 3.3 (m, 2H),2.8-2.6 (2m, 211), 2.4-2.15 (2m, 2H), 2-1.65 (m, 4H), 1.5-1.3 (m, 2H),1.41 (s, 18H), 1.35 (s, 9H), 1.19 (t, 3H), 0.7 (m, 2H)

Example 92:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-pyrazol-1-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 92 is obtained starting from intermediate 80 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.05 (d, 1H), 7.9 (d, 1H), 7.7-7.45 (m,4H), 6.6 (t, 1H), 4.25 (dd, 2H), 3.5/3.1 (2dd, 2H), 3.35/3.15 (2m, 2H),2.95 (m, 2H), 2.3/1.8 (2m, 2H), 1.9/1.5 (2m, 2H), 1.6 (m, 2H), 1.3/1.1(2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=407.1869 (407.1848)

Elemental analysis: C=56.00 (56.15); H=6.16 (6.70); N=13.77 (13.79)

Intermediate 81: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-fluoro-6-(4-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 81 is obtained starting from intermediate 21 and2-fluoro-6-(4-methoxyphenyl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.4 (d, 2H), 7.4 (dd, 1H), 7.18 (t, 1H),7.08 (d, 1H), 7 (d, 2H), 3.92 (m, 2H), 3.8 (s, 3H), 3.46 (s, 2H), 3.22(m, 2H), 2.7/2.38 (dd, 2H), 2.65/2.25 (2*m, 2H), 2-1.6 (m, 4H), 1.4 (s,18H), 1.34 (s, 9H), 1.25 (m, 2H), 1.18 (t, 3H), 0.63/0.5 (2*m, 2H)

Example 93:3-(4-Aminobutyl)-1-[[2-fluoro-6-(4-methoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 93 is obtained starting from intermediate 81 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.54 (m, 1H), 7.3 (d, 2H), 7.28 (m, 1H),7.21 (d, 1H), 7.11 (d, 2H), 4.42 (dd, 2H), 3.86 (s, 3H), 3.46/3.09 (m,2H), 3.2/2.9 (m, 2H), 2.95 (m, 2H), 2.11/1.67 (m, 2H), 1.87/1.37 (m,2H), 1.6 (m, 2H), 1.11 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=465.1955 (465.1954)

Elemental analysis: C=59.31 (59.48); H=5.75 (6.51); N=6.10 (6.03)

Intermediate 82: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(1-methylpyrazol-4-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 82 is obtained starting from intermediates 21 and 235 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.9 (s, 1H), 7.65 (s, 1H), 7.4-7.35 (m,2H), 7.3-7.2 (m, 2H), 4 (m, 2H), 3.9 (s, 3H), 3.61/3.4 (dd, 2H),3.3-3.15 (m, 2H), 2.9/2.35 (2m, 2H), 2.8/2.45 (2dd, 2H), 2.05-1.9 (m,2H), 1.8 (m, 2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.25 (m, 2H), 1.2 (t, 3H),0.65 (m, 2H)

Example 94:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(1-methylpyrazol-4-yl)phenyl]-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 94 is obtained starting from intermediate 82 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.75 (s, 1H), 7.6 (s, 1H), 7.55-7.35 (m,4H), 4.4 (dd, 2H), 3.9 (s, 3H), 3.6-3.1 (m, 3H), 3-2.8 (m, 3H), 2.05/1.7(m, 2H), 1.85/1.35 (m, 2H), 1.55 (m, 2H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=421.2016 (421.2004)

Elemental analysis: C=56.61 (57.13); H=6.36 (6.95); N=13.08 (13.33)

Intermediate 83: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-pyrimidin-5-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 83 is obtained starting from intermediates 21 and 236 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.2 (s, 1H), 8.86 (s, 2H), 7.5-7.3 (m,4H), 3.93 (m, 2H), 3.46 (dd, 2H), 3.3 (m, 2H), 2.78-2.6 (2m, 2H), 2.4(dd, 1H), 2.2 (m, 1H), 2-1.75 (m, 2H), 1.65 (m, 2H), 1.4 (m, 2H), 1.4(s, 18H), 1.33 (s, 9H), 1.18 (t, 3H), 0.6 (m, 2H)

Example 95:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-pyrimidin-5-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 95 is obtained starting from intermediate 83 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 9.19 (s, 1H), 8.85 (s, 2H), 73 (m, 1H),7.68-7.59 (m, 2H), 7.45 (m, 1H), 4.38 (dd, 2H), 3.52/3.15 (2m, 2H),3.25/2.9 (2m, 2H), 2.9 (m, 2H), 2.1/1.7 (2m, 2H), 1.85/1.4 (2m, 2H), 1.6(m, 2H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=419.1856 (419.1848)

Elemental analysis: C=57.94 (57.41); H=6.37 (6.50); N=13.40 (13.39)

Intermediate 84: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(2-methylpyrazol-3-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 84 is obtained starting from intermediates 21 and 280 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.56 (dd, 1H), 7.5 (d, 1H), 7.47 (td,1H), 7.39 (td, 1H), 7.28 (dd, 1H), 6.25 (d, 1H), 3.95 (m, 2H), 3.58 (s,3H), 3.45-3.25 (m, 4H), 2.8/2.2 (2m, 2H), 2.7/2.35 (2dd, 2H), 2-1.75 (m,4H), 1.4 (m, 2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.2 (t, 3H), 0.7 (m, 2H)

Example 96:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(2-methylpyrazol-3-yl)phenyl]-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 96 is obtained starting from intermediate 84 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7-7.4 (m, 4H), 7.63 (d, 1H), 6.45 (d,1H), 4.2 (dd, 2H), 3.58 (s, 3H), 3.55-3.05 (m, 4H), 2.8 (m, 2H), 2.1/1.7(2m, 2H), 1.85/1.4 (2m, 2H), 1.6 (m, 2H), 1.3-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=421.2019 (421.2004)

Elemental analysis: C=57.47 (57.13); H=6.44 (6.95); N=13.24 (13.33)

Intermediate 85: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(2-chlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 85 is obtained starting from intermediates 21 and 214 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.56 (m, 1H), 7.56/7.49 (d, 1H), 7.42(m, 2H), 7.42 (m, 1H), 7.34 (m, 1H), 7.27 (m, 1H), 7.12 (m, 1H), 3.92(m, 2H), 3.5-3.15 (m, 2H), 3.5-3.15 (m, 2H), 2.68/2.1 (m, 2H), 2.68/2.31(m, 2H), 2-1.7 (m, 2H), 2-1.7 (m, 2H), 1.42 (s, 18H), 1.39 (m, 2H), 1.34(s, 9H), 1.16 (2*t, 3H), 0.73 (m, 2H)

Example 97:3-(4-Aminobutyl)-1-[[2-(2-chlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 97 is obtained starting from intermediate 85 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7-7.25 (m, 4H), 7.7-7.25 (m, 4H),4.45-1.9 (m, 2H), 3.75-3 (m, 2H), 3.45-2.75 (m, 2H), 2.95 (m, 2H),2.15/1.69 (m, 2H), 1.87/1.38 (m, 2H), 1.59 (m, 2H), 1.3-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.1545 (451.1553)

Elemental analysis: C=58.81 (58.60); H=6.24 (6.26); N=6.36 (6.21)

Intermediate 86: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(2-imidazol-1-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 86 is obtained starting from intermediate 21 and2-imidazol-1-ylbenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.81 (t, 1H), 7.53 (m, 1H), 7.5-7.42(2m, 2H), 7.41 (t, 1H), 7.35 (m, 1H), 7.1 (t, 1H), 4.05-4 (m, 2H), 3.4(dd, 2H), 3.3 (m, 2H), 2.9/2.4 (2m, 2H), 2.68/2.6 (2dd, 2H), 1.9-1.6 (m,4H), 1.45 (s, 18H), 1.35 (m, 2H), 1.35 (s, 9H), 1.21 (t, 3H), 1-0.65(2m, 2H)

Example 98:3-(4-Aminobutyl)-4-hydroxy-1-[(2-imidazol-1-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 98 is obtained starting from intermediate 86 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.9 (sl, 1H), 7.7-7.45 (m, 4H), 7.36 (sl,1H), 7.25 (sl, 1H), 4.25 (dd, 2H), 3.5-3 (m, 4H), 2.95 (m, 2H), 2.1/1.7(2m, 2H), 1.85/1.4 (2m, 2H), 1.6 (m, 2H), 1.15 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=407.1852 (407.1848)

Elemental analysis: C=56.41 (56.15); H=5.89 (6.70); N=13.55 (13.79)

Intermediate 87: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-piperazin-1-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 87 is obtained starting from intermediate 21 and1-Boc-4(2-formylphenyl)piperazine in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.35 (dd, 1H), 7.24 (td, 1H), 7.11 (dd,1H), 7.07 (td, 1H), 4.1-4 (m, 2H), 3.58 (dd, 2H), 3.46 (m, 4H), 3.3 (m,2H), 2.9-2.5 (m, 8H), 1.9 (m, 2H), 1.75 (m, 2H), 1.4 (s, 18H), 1.4 (s,9H), 1.35 (s, 9H), 1.35 (m, 2H), 1.25 (t, 3H), 0.85 (m, 2H)

Example 99:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-piperazin-1-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 99 is obtained starting from intermediate 87 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6-7.25 (m, 4H), 4.3 (dd, 2H), 3.75-3.05(m, 12H), 2.9 (m, 2H), 2.2/1.75 (2m, 2H), 1.9/1.5 (2m, 2H), 1.6 (m, 2H),1.3/1.15 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]=+425.2317 (425.231768)

Elemental analysis: C=47.64 (47.53); H=6.01 (6.78); N=11.07 (11.09);Br=15.70 (15.81)

Intermediate 88: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[2-(2-oxo-1,3-oxazolidin-3-yl)phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 88 is obtained starting from intermediate 21 and2-(2-oxooxazolidin-3-yl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.5-7.3 (m, 4H), 4.5 (t, 2H), 4.15-4(m, 2H), 4-3.85 (2m, 2H), 3.5 (dd, 2H), 3.35 (m, 2H), 2.9-2.5 (m, 4H),2-1.7 (m, 4H), 1.42 (s, 18H), 1.4 (m, 2H), 1.38 (s, 9H), 1.25 (t, 3H),0.85 (m, 2H)

Example 100:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-(2-oxo-1,3-oxazolidin-3-yl)phenyl]methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 100 is obtained starting from intermediate 88 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.71-7.42 (m, 4H), 4.64 (t, 2H), 4.38 (s,2H), 4.12/4.03 (m, 2H), 3.65/3.38 (dd, 2H), 3.46/3.16 (dd, 2H), 2.94 (t,2H), 2.24/1.76 (m, 2H), 1.93/1.47 (m, 2H), 1.6 (t, 2H), 1.26/1.12 (m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=426.1782 (426.1793)

Elemental analysis: C=53.51 (53.64); H=6.34 (6.63); N=9.71 (9.88)

Intermediate 89: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(3-methylimidazol-4-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 89 is obtained starting from intermediate 21 and3-(methylimidazol-4-yl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.7 (s, 1H), 7.52 (dd, 1H), 7.4/7.35(2t, 2H), 7.25 (dd, 1H), 6.86 (s, 1H), 4.1-4 (m, 2H), 3.45-3.25 (m, 2H),3.4 (s, 3H), 3.35 (m, 2H), 2.95/2.4 (2m, 2H), 2.85-2.6 (2m, 2H),1.95-1.8 (m, 2H), 1.75 (m, 2H), 1.45 (s, 18H), 1.4 (m, 2H), 1.35 (s,9H), 1.25 (t, 3H), 0.9-0.7 (2m, 2H)

Example 101:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(3-methylimidazol-4-yl)phenyl]-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 101 is obtained starting from intermediate 89 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.8 (s, 1H), 7.65 (m, 1H), 7.59 (m, 2H),7.45 (m, 1H), 7.08 (d, 1H), 4.24 (dl, 2H), 3.43 (s, 3H), 3.36/3.02 (dd,2H), 3.19 (m, 2H), 2.94 (m, 2H), 2.15/1.73 (m, 2H), 1.9/1.44 (m, 2H),1.6 (m, 2H), 1.15 (dl, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=421.1999 (421.2004)

Elemental analysis: C=58.05 (57.13); H=6.09 (6.95); N=13.62 (13.33)

Intermediate 90: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(1-methylimidazol-2-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 90 is obtained starting from intermediates 21 and 223 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.55 (dd, 1H), 7.45/7.35 (2t, 2H), 7.31(dd, 1H), 7.25 (d, 1H), 6.98 (d, 1H), 4 (m, 2H), 3.5 (dd, 2H), 3.48 (s,3H), 3.4 (m, 21-1), 2.95/2.35 (2m, 2H), 2.7-2.4 (2m, 2H), 1.85-1.75 (m,2H), 1.7 (m, 2H), 1.45 (s, 18H), 1.4 (m, 2H), 1.35 (s, 9H), 1.2 (t, 3H),0.85 (m, 2H)

Example 102:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(1-methylimidazol-2-yl)phenyl]-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 102 is obtained starting from intermediate 90 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7-7.5 (m, 4H), 7.23 (d, 1H), 7.16 (d,1H), 4.17 (dd, 2H), 3.61 (s, 3H), 3.46/3.26 (2m, 2H), 3.37/3.09 (dd,2H), 2.8 (m, 2H), 2.11/1.83 (2m, 2H), 1.94/1.4 (2m, 2H), 1.5 (m, 2H), 1(m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=421.2013 (421.2004)

Elemental analysis: C=57.28 (57.13); H=7.10 (6.95); N=13.21 (13.33)

Intermediate 91: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(4-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 91 is obtained starting from intermediates 21 and 221 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.48 (dd, 1H), 7.33 (d, 2H), 7.16 (td,1H), 7.02 (dd, 1H), 7.02 (d, 2H), 4.03 (m, 2H), 3.8 (s, 3H), 3.4 (AB,2H), 3.32 (m, 2H), 2.66/2.51/2.41 (3m, 4H), 1.91-1.66 (m, 4H), 1.41 (s,18H), 1.37 (m, 2H), 1.34 (s, 9H), 1.22 (t, 3H), 0.88/0.76 (2m, 2H)

Example 103:3-(4-Aminobutyl)-1-[[4-fluoro-2-(4-methoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 103 is obtained starting from intermediate 91 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.62 (dd, 1H), 7.35 (d, 2H), 7.24 (td, 1H),7.17 (dd, 1H), 7.13 (d, 2H), 4.36 (AB, 2H), 3.89 (s, 3H), 3.37/3.14 (2m,2H), 3.14/2.85 (2m, 2H), 2.97 (m, 2H), 2.09/1.66 (2m, 2H), 1.88/1.38(2m, 2H), 1.62 (m, 2H), 1.09 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=465.1965 (465.1954)

Elemental analysis: C=59.91 (59.48); H=6.23 (6.51); N=6.25 (6.03)

Example 104:3-(4-Aminobutyl)-1-[[4-fluoro-2-(4-hydroxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 104 is obtained starting from intermediate 91 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.62 (dd, 1H), 7.3 (d, 2H), 7.25 (td, 1H),7.18 (dd, 1H), 7.03 (d, 2H), 4.39 (AB, 2H), 3.4/3.13 (2m, 2H), 3.18/2.88(2m, 2H), 2.99 (m, 2H), 2.12/1.68 (2m, 2H), 1.89/1.38 (2m, 2H), 1.63 (m,2H), 1.12 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.1816 (451.1798)

Elemental analysis: C=58.99 (58.66); H=6.33 (6.27); N=6.27 (6.22)

Intermediate 92: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-phenylthiophen-3-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 92 is obtained starting from intermediates 21 and 224 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.55-7.34 (m, 5H), 7.55-7.34 (m, 1H),7.09 (d, 1H), 4.04 (m, 2H), 3.51 (dd, 2H), 3.34 (m, 2H), 2.88-2.52 (m,4H), 1.91 (m, 2H), 1.74 (m, 2H), 1.41 (s, 18H), 1.38 (m, 2H), 1.35 (s,9H), 1.23 (t, 3H), 0.89 (m, 2H)

Example 105:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-phenylthiophen-3-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 105 is obtained starting from intermediate 92 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.52 (d, 1H), 7.4 (m, 5H), 7.2 (d, 1H),4.4-4.25 (m, 2H), 3.6-3.4 (m, 1H), 3.2-3.1 (m, 2H), 2.9 (m, 2H), 2.7 (m,1H), 2.15 (m, 1H), 1.85 (m, 1H), 1.65-1.5 (m, 3H), 1.3 (m, 1H), 1 (m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=423.1511 (423.1507)

Elemental analysis: C=56.99 (56.86); H=6.31 (6.44); N=6.79 (6.63);S=7.29 (7.59)

Intermediate 93: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(4-phenylthiophen-3-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 93 is obtained starting from intermediates 21 and 252 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.53 (d, 2H), 7.5/7.47 (2d, 2H), 7.41(t, 2H), 7.33 (t, 1H), 4.04 (m, 2H), 3.47 (AB, 2H), 3.32 (m, 2H),2.92-2.4 (m, 4H), 1.94-1.6 (m, 4H), 1.43/1.41 (2s, 18H), 1.34 (2s, 9H),1.33 (m, 2H), 1.22 (t, 3H), 0.8 (m, 2H)

Example 106:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(4-phenylthiophen-3-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 106 is obtained starting from intermediate 93 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.75 (d, 1H), 7.45 (m, 5H), 7.42 (d, 1H),4.4-4.3 (2*d, 2H), 3.45/3.15 (m, 2H), 3.15/2.75 (m, 2H), 2.9 (m, 2H),2.1 (m, 1H), 1.8 (m, 1H), 1.7-1.5 (m, 3H), 1.25 (m, 1H), 0.95 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=423.1503 (423.1507)

Elemental analysis: C=57.35 (56.86); H=6.30 (6.44); N=6.53 (6.63);S=7.56 (7.59)

Intermediate 94: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-(thiophen-2-ylmethyl)-1,4-azaphosphinane-3-carboxylate

Intermediate 94 is obtained starting from intermediate 21 and2-formylthiophene in accordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.43 (m, 1H), 6.97 (m, 2H), 4.05 (m,2H), 3.77 (AB, 2H), 3.41 (m, 2H), 2.85/2.55 (2m, 2H), 2.85/2.66 (2m,2H), 2-1.7 (m, 4H), 1.43 (s, 18H), 1.41 (m, 2H), 1.39 (s, 9H), 1.24 (t,3H), 1.01 (m, 2H)

Example 107:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(thiophen-2-ylmethyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 107 is obtained starting from intermediate 94 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (dl, 1H), 7.25 (dl, 1H), 7.12 (t, 1H),4.6/4.5 (d, 2H), 3.75/3.3 (m, 2H), 3.6/3.12 (m, 2H), 2.95 (m, 2H),2.25/1.8 (m, 2H), 1.95/1.5 (m, 2H), 1.6 (m, 2H), 1.3-1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=347.1205 (347.1194)

Elemental analysis: C=48.94 (48.55); H=5.79 (6:69); N=7.90 (8.09);S=9.22 (9.26)

Intermediate 95: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[2-(1,3-thiazol-2-yl)phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 95 is obtained starting from intermediates 21 and 225 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.98 (d, 1H), 7.85 (d, 1H), 7.7 (d,1H), 4.45 (m, 3H), 4.05 (quad., 2H), 3.45/3.35 (d, 2H), 3.4/2.5 (m, 2H),3.3 (m, 2H), 2.7/2.5 (m, 2H), 1.8-1.55 (m, 4H), 1.45-1.35 (m, 2H),1.4/1.3 (s, 27H), 1.2 (t, 3H), 0.65-0.3 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=708.3453 (708.3447)

Example 108:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-(1,3-thiazol-2-yl)phenyl]-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 108 is obtained starting from intermediate 95 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.98 (m, 2H), 7.85 (m, 4H), 4.6 (d, 1H),4.2 (d, 1H), 3.85 (m, 1H), 3.45 (m, 2H), 3.15 (dd, 1H), 2.9 (m, 2H), 2.3(m, 1H), 1.85 (m, 2H), 1.55 (m, 3H), 1.2 (m, 1H), 1.0 (m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=424.1443 (424.1459)

Elemental analysis: C=54.17 (53.89); H=5.57 (6.19); N=9.91 (9.92);S=7.38 (7.57)

Intermediate 96: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(2-naphthalen-1-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 96 is obtained starting from intermediates 21 and 228 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8-7.15 (m, 11H), 4.05-3.8 (m, 2H),3.5-3.3 (m, 2H), 3.3-3 (dd, 2H), 2.7-2.1 (m, 4H), 2-1.5 (m, 4H), 1.5-1.3(m, 2H), 1.45 (s, 18H), 1.35 (s, 9H), 1.2 (t, 3H), 1-0.5 (m, 2H)

Example 109:3-(4-Aminobutyl)-4-hydroxy-1-[(2-naphthalen-1-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 109 is obtained starting from intermediate 96 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8 (d, 2H), 7.75-7.3 (m, 9H), 4.3/4.05 (2*d,1H), 3.95/3.8 (2*d, 1H), 3.55-2.8 (m, 5H), 2.65 (m, 1H), 2.2-1.9 (m,1H), 1.75 (m, 1H), 1.7-1.4 (m, 3H), 1.35-0.7 (m, 3H)

ESI/FIA/HR and MS/MS: [M+H]+=467.2109 (467.2099)

Elemental analysis: C=67.08 (66.94); H=6.21 (6.70); N=5.75 (6.00)

Intermediate 97: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(4-phenylthiophen-2-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 97 is obtained starting from intermediate 21 and4-phenyl-2-thiophenecarboxaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (500 MHz, dmso-d6) δ ppm 7.75 (d, 1H), 7.67 (d, 2H), 7.41 (d,1H), 7.39 (t, 2H), 7.27 (t, 1H), 4.07 (m, 2H), 3.8 (AB, 2H), 3.4 (m,2H), 2.95/2.58 (2m, 2H), 2.89/2.71 (2m, 2H), 2-1.74 (m, 4H),1.43/1.4/1.39/1.37 (5s, 27H), 1.4 (m, 2H), 1.24/1.2 (2t, 3H), 1.1/1 (2m,2H)

Example 110:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(4-phenylthiophen-2-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 110 is obtained starting from intermediate 97 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.75 (s, 1H), 7.65 (d, 2H), 7.6 (s, 1H),7.42 (d, 2H), 7.3 (t, 1H), 4.6/4.5 (2*d, 2H), 3.8-3.35 (m, 3H), 3.1 (m,1H), 2.85 (m, 2H), 2.25/1.8 (m, 2H), 1.95/1.45 (m, 2H), 1.55 (m, 2H),1.25-1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=423.151 (423.1507)

Elemental analysis: C=57.05 (56.86); H=6.10 (6.44); N=6.67 (6.63);S=7.51 (7.59)

Intermediate 98: tert-Butyl3-(4-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(2-bromo-4-hydroxyphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 98 is obtained starting from intermediate 21 and2-bromo-4-methoxybenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.3 (d, 1H), 7.2 (s, 1H), 6.95 (dd,1H), 4.05 (m, 2H), 3.75 (s, 3H), 3.6-3.5 (d, 2H), 3.4-3.3 (m, 2H), 3-2.6(m, 4H), 2.9-1:5 (m, 4H), 1.42/135 (s, 27H), 1.4 (m, 2H), 1.22 (t, 3H),0.75 (m, 2H)

³¹P NMR: (300 MHz, dmso-d6) δ ppm 47.5

Example 111:3-(4-Aminobutyl)-1-[(2-bromo-4-hydroxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 111 is obtained starting from intermediate 98 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.38 (d, 1H), 7.2 (s, 1H), 6.9 (dd, 1H),4.4-4.3 (2*d, 2H), 3.8-3.7 (m, 1H), 3.6-3.4 (m, 2H), 3.25 (dd, 1H), 2.95(m, 2H), 2.25 (m, 1H), 1.95 (m, 1H), 1.8 (m, 1H), 1.65-1.5 (m, 3H), 1.3(m, 1H), 1.15 (m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=435.067 (435.0684)

Elemental analysis: C=44.16 (44.15); H=5.06 (5.56); N=6.05 (6.44)

Intermediate 99: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(4-chlorophenyl)pyridin-3-yl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 99 is obtained starting from intermediates 21 and 291 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.58 (m, 1H), 7.9/7.89 (2dd, 1H),7.63/7.61 (2d, 2H), 7.53 (d, 2H), 7.4 (dd, 1H), 4.04/3.94 (2m, 2H),3.56/3.53 (2AB, 2H), 3.32 (m, 2H), 2.76-2.25 (m, 4H), 1.95-1.65 (m, 4H),1.43/1.41 (2s, 18H), 1.35 (m, 2H), 1.33/1.32 (2s, 9H), 1.23/1.18 (2t,3H), 0.9/0.74 (2m, 2H)

Example 112:3-(4-Aminobutyl)-1-[[2-(4-chlorophenyl)pyridin-3-yl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 112 is obtained starting from intermediate 99 in accordance withprocedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 8.61 (dd, 1H), 8.09 (dd, 1H), 7.56/7.43(2d, 4H), 7.55 (dd, 1H), 4.42 (AB, 2H), 3.45/3.1 (2m, 2H), 3.1/2.87 (2m,2H), 2.9 (m, 2H), 2.1/1.65 (2m, 2H), 1:82/1.33 (2m, 2H), 1.55 (m, 2H),1.03 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=452.1508 (452.1505)

Elemental analysis: C=55.90 (55.82); H=6.11 (6.02); N=8.95 (9.30)

Intermediate 100: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[4-chloro-2-(4-chlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 100 is obtained starting from intermediates 21 and 292 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.55-7.35 (m, 6H), 7.25 (s, 1H), 4.15-4(m, 2H), 3.5-3.3 (m, 4H), 2.95-2.4 (m, 4H), 1.95-1.6 (m, 6H), 1.5-1.3(3t, 27H), 1.25 (t, 3H), 1.15-0.75 (m, 2H)

Example 113:3-(4-Aminobutyl)-1-[[4-chloro-2-(4-chlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 113 is obtained starting from intermediate 100 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.58 (d, 1H), 7.54 (d, 2H), 7.54 (dd, 1H),7.45 (d, 1H), 7.33 (d, 2H), 4.33 (dd, 2H), 3.41/3.1 (2m, 2H), 3.15/2.85(dd, 2H), 2.95 (m, 2H), 2.1/1.65 (2m, 2H), 1.85/1.35 (2m, 2H), 1.6 (m,2H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=485.1172 (485.1163)

Elemental analysis: C=54.57 (54.44); H=5.31 (5.61); N=5.84 (5.77)

Intermediate 101: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[2-(2-phenylphenyl)phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 101 is obtained starting from intermediates 21 and 238 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.6-7 (m, 13H), 4.15-3.9 (m, 2H),3.5-3.3 (m, 2H), 3.3-2.9 (m, 2H), 2.75-2.2 (m, 4H), 1.95-1.65 (m, 4H),1.6-1.3 (m, 2H), 1.45 (3s, 27H), 1.25 (t, 3H), 1.2-0.7 (m, 2H)

Example 114:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-(2-phenylphenyl)phenyl]-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 114 is obtained starting from intermediate 101 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6-7.1 (m, 13H), 3.8/3.6/3.55 (2*d, 2H),3.3/3 (2*m, 2H), 3.15/2.6 (2*m, 2H), 2.92 (m, 2H), 2.05/1.6 (2*m, 2H),1.8/1.3 (2*m, 2H), 1.6 (m, 2H), 1.02 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=493.2273 (493.2256)

Elemental analysis: C=68.12 (68.28); H=6.31 (6.75); N=5.77 (5.69)

Intermediate 102: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[2-[3-(trifluoromethoxy)phenyl]phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 102 is obtained starting from intermediate 21 and2-[3-(trifluoromethoxyphenyl)]benzaldehyde in accordance with procedureF described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.59 (t, 1H), 7.42 (m, 3H), 7.42 (m,3H), 7.28 (m, 1H), 3.99 (m, 2H), 3.54/3.32 (m, 2H), 3.32 (m, 2H),3.1-2.2 (m, 2H), 3.1-2.2 (m, 2H), 2-1.6 (m, 2H), 2-1.6 (m, 2H), 1.5-1.3(m, 27H), 1.3 (m, 2H), 1.21 (t, 3H), 0.9-0.5 (m, 2H)

Example 115:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-[3-(trifluoromethoxy)phenyl]-phenyl]methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 115 is obtained starting from intermediate 102 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.63 (m, 1H), 7.59 (t, 1H), 7.55 (m,2H), 7.41 (m, 1H), 7.41 (m, 1H), 7.34 (m, 2H), 4.41/3.2 (2*d, 2H),3.43/3.1 (m, 2H), 3.2/2.84 (m, 2H), 2.94 (m, 2H), 2.11/1.64 (m, 2H),1.86/1.36 (m, 2H), 1.59 (m, 2H), 1.13/1.06 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=501.1759 (501.1766)

Elemental analysis: C=54.63 (55.20); H=5.24 (5.64); N=5.43 (5.60)

Intermediate 103: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-fluoro-2-phenylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 103 is obtained starting from intermediates 21 and 257 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 22/2.7 (2*m, 2H), 7.52 (dd, 1H), 7.47(t, 2H), 7.4 (t, 1H), 7.37 (d, 2H), 7.2 (dt, 1H), 7.04 (dd, 1H), 4-3.7(m, 2H), 3.52/3.32 (2*d, 2H), 3.32 (m, 2H), 2.7/232 (2*m, 2H), 1.95-1.72(m, 2H), 1.95-1.72 (m, 2H), 1.41/1.35 (2*s, 27H), 1.38 (m, 2H), 1.17 (t,3H), 0.8-0.6 (m, 2H)

Example 116:3-(4-Aminobutyl)-1-[(4-fluoro-2-phenylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 116 is obtained starting from intermediate 103 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6 (dd, 1H), 7.49 (m, 3H), 7.34 (m, 2H),7.22 (td, 1H), 7.15 (dd, 1H), 4.31 (AB, 2H), 3.32/3.06 (2m, 2H),3.16/2.8 (2m, 2H), 2.92 (m, 2H), 2.05/1.6 (2m, 2H), 1.82/1.33 (2m, 2H),1.56 (m, 2H), 1.07 (m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −111.5

ESI/FIA/HR and MS/MS: [M+H]+=435.1854 (435.1848)

Elemental analysis: C=60.79 (60.82); H=6.07 (6.50); N=6.19 (6.45)

Intermediate 104: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-hydroxy-2-phenylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 104 is obtained starting from intermediates 21 and 285 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.45-7.32 (m, 5H), 7.42 (d, 1H), 6.95(dd, 1H), 6.74 (df, 1H), 3.92 (m, 2H), 3.77 (s, 3H), 3.46/3.27 (2*d,2H), 3.34 (m, 2H), 2.75/2.15 (2*m, 2H), 2.68/2.28 (2*m, 2H), 1.85-1.65(m, 2H), 1.85-1.65 (m, 2H), 1.69 (m, 2H), 1.41/1.34 (2*s, 27H), 1.39 (m,2H), 1.17 (t, 3H)

Example 117:3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxy-2-phenylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 117 is obtained starting from intermediate 104 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5-7.25 (m, 5H), 7.3 (d, 1H), 6.92 (dd,1H), 6.82 (d, 1H), 4.3/4.15 (2*d, 2H), 3.3/3 (2*m, 2H), 3.15/2.72 (dd,2H), 2.9 (m, 2H), 2/1.55 (2*m, 2H), 1.8/1.55 (2*m, 2H), 1.55/1.3 (2*m,2H), 1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=433.1888 (433.1892)

Elemental analysis: C=60.92 (61.10); H=6.44 (6.76); N=6.43 (6.48)

Intermediate 105: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(furan-2-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 105 is obtained starting from intermediate 21 and2-(2-furyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.77 (d, 1H), 7.62 (d, 1H), 7.41 (d,1H), 7.37/7.31 (2*m, 2H), 6.77 (d, 1H), 6.61 (dd, 1H), 3.96 (m, 2H),3.84/3.49 (2*d, 2H), 3.3-3.15 (m, 2H), 2.95/2.38 (2*m, 2H), 2.77/2.45(2*m, 2H), 2.05-1.6 (m, 2H), 2.05-1.6 (m, 2H), 1.4/1.32 (2*s, 27H),1.3-1.15 (m, 2H), 1.2 (t, 3H), 0.7-0.48 (4*m, 2H)

Example 118:3-(4-Aminobutyl)-1-[[2-(furan-2-yl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 118 is obtained starting from intermediate 105 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.75 (d, 1H), 7.73 (s, 1H), 7.52 (t, 1H),7.48 (d, 1H), 7.4 (t, 1H), 6.88 (d, 1H), 6.63 (d, 1H), 4.63/433 (2*d,2H), 3.82/3.5 (2*m, 2H), 3.48/3.18 (dd, 2H), 2.9 (m, 2H), 2.26/1.8 (2*m,2H), 1.9/1.48 (2*m, 2H), 1.6 (m, 2H), 1.2/1.05 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=407.1729 (407.1735)

Elemental analysis: C=59.18 (59.11); H=6.65 (6.70); N=6.86 (6.89)

Intermediate 106: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-thiophen-2-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 106 is obtained starting from intermediate 21 and2-(2-thienyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.62 (dd, 1H), 7.46-7.33 (m, 4H), 7.23(dd, 1H), 7.14 (dd, 1H), 4.03-3.88 (m, 2H), 3.65/3.42 (2*d, 2H),3.32-3.15 (m, 2H), 3-2.7/2.4 (2*m, 2H), 3-2.7/2.4 (2*m, 2H), 2.05-1.75(m, 2H), 2.05-1.75 (m, 2H), 1.4/1.34 (2*s, 27H), 1.39 (m, 2H), 1.2 (t,3H), 0.7-0.45 (m, 2H)

Example 119:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-thiophen-2-ylphenyl)-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 119 is obtained starting from intermediate 106 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (m, 1H), 7.57 (d, 1H), 7.52 (m, 2H),7.52. (m, 1H), 7.2 (d, 1H), 7.15 (d, 1H), 4.52/4.42 (2*d, 2H), 3.48/3.22(2*m, 2H), 3.3/2.98 (dd, 2H), 2.93 (m, 2H), 2.13/1.68 (2*m, 2H),1.88/1.4 (2*m, 2H), 1.6 (m, 2H), 1.2/1.05 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=423.1493 (423.1507)

Elemental analysis: C=56.66 (56.86); H=6.32 (6.44); N=6.64 (6.63);S=7.48 (7.59)

Intermediate 107: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-pyridin-4-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 107 is obtained starting from intermediates 21 and 258 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.62 (d, 2H), 7.5 (dd, 1H), 7.46-7.37(m, 2H), 7.4 (d, 2H), 7.26 (dd, 1H), 3.92 (m, 2H), 3.58/3.38 (2*d, 2H),3.3 (m, 2H), 2.82/2.22 (2*m, 2H), 2.68/2.37 (2*m, 2H), 1.85-1.65 (m,2H), 1.85-1.65 (m, 2H), 1.41/1.33 (2*s, 27H), 1.38 (m, 2H), 1.18 (t,3H), 0.63 (m, 2H)

¹³C NMR: (400 MHz, dmso-d6) δ ppm 107, 67, 29/23

Example 120:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-pyridin-4-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 120 is obtained starting from intermediate 107 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.59 (d, 2H), 7.62 (m, 1H), 7.55 (m, 2H),7.41 (d, 2H), 7.41 (m, 1H), 4.4/4.29 (2*d, 2H), 3.42/3.09 (2*m, 2H),3.18/2.85 (2*m, 2H), 2.91 (m, 2H), 2.08/1.65 (2*m, 2H), 1.82/1.55 (2*m,2H), 1.55/1.32 (2*m, 2H), 1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=418.1891 (418.1895)

Elemental analysis: C=59.87 (60.42); H=6.51 (6.76); N=9.86 (10.07)

Intermediate 108: tert-Butyl 3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-pyridin-3-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 108 is obtained starting from intermediate 21 and2-(3-pyridyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.58 (dd, 1H), 8.56 (d, 1H), 7.81 (dt,1H), 7.48 (m, 1H), 7.48 (m, 1H), 7.41 (m, 2H), 7.27 (d, 1H), 3.93 (m,2H), 3.55/3.35 (2*d, 2H), 3.29 (m, 2H), 2.71/2.2 (m, 2H), 2.71/2.35 (m,2H), 1.95-1.7 (m, 2H), 1.95-1.7 (m, 2H), 1.41 (s, 18H), 1.36 (m, 2H),1.34 (s, 9H), 1.18 (t, 3H), 0.64 (m, 2H)

Example 121:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-pyridin-3-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 121 is obtained starting from intermediate 108 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.58 (dd, 1H), 8.51 (d, 1H), 7.86 (dt, 1H),7.67 (m, 1H), 7.58 (m, 1H), 7.58 (m, 2H), 7.43 (m, 1H), 4.42/4.3 (2*d,2H), 3.46/3.11 (m, 2H), 3.2/2.87 (m, 2H), 2.94 (m, 2H), 2.11/1.65 (m,2H), 1.86/1.36 (m, 2H), 1.59 (m, 2H), 1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=418.1898 (418.1895)

Elemental analysis: C=60.58 (60.42); H=6.51 (6.76); N=10.09 (10.07)

Intermediate 109: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[2-[4-(trifluoromethyl)phenyl]phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 109 is obtained starting from intermediate 21 and2-[4-(trifluoromethyl)phenyl]benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.81 (d, 2H), 7.62 (d, 2H), 7.5 (d,1H), 7.41 (m, 2H), 7.27 (d, 1H), 3.93 (m, 2H), 3.58/3.34 (2*d, 2H), 3.28(m, 2H), 2.74/2.36 (m, 2H), 2.74/2.24 (m, 2H), 2-1.7 (m, 2H), 2-1.7 (m,2H), 1.4 (s, 18H), 1.36 (m, 2H), 1.34 (s, 9H), 1.17 (t, 3H), 0.65 (m,2H)

Example 122:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-[4-(trifluoromethyl)phenyl]-phenyl]methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 122 is obtained starting from intermediate 109 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.83 (d, 2H), 7.64 (m, 1H), 7.56 (m, 2H),7.53 (d, 2H), 7.43 (m, 1H), 4.42/4.28 (2*d, 2H), 3.42/3.09 (m, 2H),3.18/2.84 (m, 2H), 2.94 (m, 2H), 2.1/1.64 (m, 2H), 1.85/1.35 (m, 2H),1.59 (m, 2H), 1.13/1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=485.1800 (485.1817)

Elemental analysis: C=56.24 (57.02); H=5.26 (5.83); N=5.65 (5.78)

Intermediate 110: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(2-cyclohexylphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 110 is obtained starting from intermediate 21 and2-cyclohexylbenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.28/7.17 (2*d, 2H), 7.22/7.1 (2*m,2H), 3.98 (m, 2H), 3.5 (s, 2H), 3.31 (m, 2H), 3-2.8/2.28 (2*m, 2H),3-2.8/2.5 (2*m, 2H), 3-2.8 (m, 1H), 2-1.78 (2*m, 2H), 1.9-1.65 (m, 2H),1.9-1.65 (m, 6H), 1.45-1.25 (m, 2H), 1.45-1.25 (m, 4H), 1.41/1.37 (2*s,27H), 1.21 (t, 3H), 0.85-0.65 (m, 2H)

Example 123:3-(4-Aminobutyl)-1-[(2-cyclohexylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 123 is obtained starting from intermediate 110 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.52-7.4 (m, 2H), 7.52-7.4/7.3 (2*m, 2H),4.4 (t, 2H), 3.6/3.4 (2*m, 2H), 3.49/3.24 (2*m, 2H), 2.93 (m, 2H), 2.66(m, 1H), 2.21/1.75 (2*m, 2H), 1.95/1.5 (2*m, 2H), 1.85-1.1 (m, 10H),1.85-1.1 (m, 4H)

ESI/FIA/HR and MS/MS: [M+H]+=423.2408 (423.2412)

Elemental analysis: C=62.46 (62.54); H=8.23 (8.35); N=6.61 (6.63)

Intermediate 111: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-(1H-indazol-5-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 111 is obtained starting from intermediate 21 and1H-indazole-5-carbaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13 (sl, 1H), 8 (s, 1H), 7.62 (df, 1H),7.48 (d, 1H), 7.3 (dd, 1H), 3.97 (m, 2H), 3.72/3.52 (2*d, 2H), 3.4-3.2(m, 2H), 2.96/2.32 (2*m, 2H), 2.83/2.47 (2*m, 2H), 2-1.8 (m, 2H), 2-1.8(m, 2H), 1.39/1.33 (2*s, 27H), 1.36 (m, 2H), 1.2 (t, 3H), 0.9-0.7 (m,2H)

Example 124:3-(4-Aminobutyl)-4-hydroxy-1-(1H-indazol-5-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 124 is obtained starting from intermediate 111 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.16 (s, 1H), 7.91 (s, 1H), 7.68 (d, 1H),7.49 (d, 1H), 4.51/4.32 (2*d, 2H), 3.64/3.35 (2*m, 2H), 3.48/3.11 (2*m,2H), 2.89 (m, 2H), 2.25/1.77 (2*m, 2H), 1.91/1.55 (2*m, 2H), 1.55/1.45(2*m, 2H), 1.19/1.05 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=381.1697 (381.1691)

Elemental analysis: C=53.27 (53.68); H=6.55 (6.62); N=14.52 (14.73)

Intermediate 112: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-thiophen-3-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 112 is obtained starting from intermediates 21 and 259 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.61 (dd, 1H), 7.59 (dd, 1H), 7.44/7.32(2*m, 4H), 7.25 (dd, 1H), 3.95 (m, 2H), 3.6/3.4 (2*d, 2H), 33 (m, 2H),2.8/2.29 (2*m, 2H), 2.8/2.4 (2*m, 2H), 2-1.79 (m, 2H), 2-1.79 (m, 2H),1.7 (m, 2H), 1.4/1.34 (2*s, 27H), 1.35 (m, 2H), 1.19 (t, 3H)

Example 125:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-thiophen-3-ylphenyl)-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 125 is obtained starting from intermediate 112 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.63-7.43 (m, 2H), 7.63-7.43 (m, 4H), 7.19(dd, 1H), 4.49/4.34 (2*d, 2H), 3.39/3.17 (2*m, 2H), 3.25/2.94 (2*m, 2H),2.94 (m, 2H), 2.1/1.68 (2*m, 2H), 1.87/1.59 (2*m, 2H), 1.59/1.39 (2*m,2H), 1.18/1.05 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=423.1504 (423.1507)

Elemental analysis: C=57.17 (56.86); H=6.48 (6.44); N=6.67 (6.63);S=7.11 (7.59)

Intermediate 113: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(3-fluorophenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 113 is obtained starting from intermediate 21 and2-(3-fluorophenyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.48 (m, 1H), 7.48 (m, 1H), 7.38 (m,2H), 7.23 (m, 3H), 7.23 (m, 1H), 3.93 (m, 2H), 3.56/3.36 (2*d, 2H), 3.29(m, 2H), 2.73/2.36 (m, 2H), 2.73/2.23 (m, 2H), 2-1.7 (m, 2H), 2-1.7 (m,2H), 1.41 (s, 18H), 1.36 (m, 2H), 133 (s, 9H), 1.17 (t, 3H), 0.66 (m,2H)

Example 126:3-(4-Aminobutyl)-1-[[2-(3-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 126 is obtained starting from intermediate 113 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.62 (m, 1H), 7.54 (m, 2H), 7.5 (m, 1H),7.41 (m, 1H), 7.21 (m, 1H), 7.16 (m, 1H), 7.14 (m, 1H), 4.44/4.31 (2*d,2H), 3.43/3.11 (m, 2H), 3.21/2.86 (m, 2H), 2.94 (m, 2H), 2.11/1.64 (m,2H), 1.86/1.36 (m, 2H), 1.59 (m, 2H), 1.09 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=435.1841 (435.1848)

Elemental analysis: C=61.58 (60.82); H=5.84 (6.50); N=6.51 (6.45)

Intermediate 114: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(5-phenyl-1,2-oxazol-4-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 114 is obtained starting from intermediates 21 and 219 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.6 (s, 1H), 7.9 (m, 2H), 7.55 (m, 3H),4 (m, 2H), 3.6 (dd, 2H), 3.3 (m, 2H), 3/2.35 (2m, 2H), 2.8/2.5 (2dd,2H), 2 (m, 2H), 1.8 (m, 2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.35 (m, 2H),1.2 (t, 3H), 0.8 (m, 2H)

Example 127:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(5-phenyl-1,2-oxazol-4-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 127 is obtained starting from intermediate 114 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.66 (s, 1H), 7.75-7.55 (m, 5H), 4.5 (dd,2H), 3.6/3.28 (2m, 2H), 3.2/2.9 (dd, 2H), 2.85 (m, 2H), 2.2/1.7 (2m,2H), 1.85/1.25 (2m, 2H), 1.5 (m, 2H), 0.9/0.7 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=408.1661 (408.1688)

Intermediate 115: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[(5-bromo-2-phenylphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 115 is obtained starting from intermediate 21 and5-bromo-2-phenylbenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.71 (df, 1H), 7.53 (dd, 1H), 7.45 (t,2H), 7.4 (dd, 1H), 7.3 (d, 2H), 7.16 (t, 1H), 3.92 (m, 2H), 3.58/3.35(2*d, 2H), 3.4 (m, 2H), 2.74/2.22 (2*m, 2H), 2.67/2.34 (2*m, 2H), 2-1.7(m, 2H), 2-1.7 (m, 2H), 1.42 (m, 2H), 1.4/1.35 (2*s, 27H), 1.17 (t, 3H),0.78 (m, 2H)

Example 128:3-(4-Aminobutyl)-1-[(5-bromo-2-phenylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 128 is obtained starting from intermediate 115 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.81 (d, 1H), 7.7 (dd, 1H), 7.52 (t, 2H),7.49 (t, 1H), 7.37 (d, 2H), 7.31 (d, 1H), 4.4/4.28 (2*d, 2H), 3.32/2.88(2*m, 2H), 3.2/3.1 (2*m, 2H), 2.95 (m, 2H), 2.08/1.67 (2*m, 2H),1.88/1.6 (2*m, 2H), 1.6/1.37 (2*m, 2H), 1.17/1.08 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=495.1041 (495.1048)

Elemental analysis: C=53.71 (53.34); H=5.72 (5.70); N=5.89 (5.66)

Intermediate 116: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[2-[4-(trifluoromethoxy)phenyl]phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 116 is obtained starting from intermediates 21 and 286 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.65-7.33 (m, 4H), 7.65-7.33 (m, 3H),7.25 (dd, 1H), 3.94 (m, 2H), 3.57/3.3 (2*d, 2H), 3.3 (m, 2H), 2.72/2.23(2*m, 2H), 2.72/2.37 (2*m, 2H), 2-1.7 (m, 2H), 2-1.7 (m, 2H), 1.4/1.34(2*s, 24H), 1.35 (m, 2H), 1.17 (t, 3H), 0.65 (m, 2H)

Example 129:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-[4-(trifluoromethoxy)-phenyl]phenyl]methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 129 is obtained starting from intermediate 116 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.62 (m, 1H), 7.54 (m, 2H), 7.44 (s, 4H),7.4 (m, 1H), 4.42/4.28 (2*d, 2H), 3.4/3.12 (2*m, 2H), 3.2/2.88 (2*m,2H), 2.94 (m, 2H), 2.1/1.64 (2*m, 2H), 1.86/1.59 (2*m, 2H), 1.59/1.38(2*m, 2H), 1.15/1.05 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=501.1773 (501.1766)

Elemental analysis: C=55.71 (55.20); H=5.27 (5.64); N=5.62 (5.60)

Intermediate 117: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 117 is obtained starting from intermediates 21 and 271 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1H), 7.42 (dd, 2H), 7.29 (t,2H), 7.21 (dt, 1H), 7.06 (dd, 1H), 3:93 (m, 2H), 3.49/3.3 (2*d, 2H), 3.3(m, 2H), 2.72/2.21 (2*m, 2H), 2.69/2.34 (2*m, 2H), 1.95-1.7 (unresolvedpeak, 2H), 1.95-1.7 (unresolved peak, 2H), 1.68 (m, 2H), 1.41/1.33 (2*s,27H), 1.38 (m, 2H), 1.18 (t, 3H)

Example 130:3-(4-Aminobutyl)-1-[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 130 is obtained starting from intermediate 117 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.66 (dd, 1H), 7.38 (dd, 2H), 7.27 (t, 2H),7.25 (df, 1H), 7.18 (dd, 1H), 4.39/4.28 (2*d, 2H), 3.38/3.09 (2*m, 2H),3.18/2.87 (2*m, 2H), 2.95 (m, 2H), 2.09/1.68 (2*m, 2H), 1.86/1.6 (2*m,2H), 1.6/1.37 (2*m, 2H), 1.15/1.07 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=453.1741 (453.1754)

Elemental analysis: C=58.67 (58.40); H=5.99 (6.01); N=6.46 (6.19)

Intermediate 118: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-[4-chloro-3-(trifluoromethyl)phenyl]phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 118 is obtained starting from intermediates 21 and 278 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.9 (d, 1H), 7.81 (d, 1H), 7.75 (dd,1H), 7.42/7.32 (2m, 3H), 3.95 (m, 2H), 3.41 (AB, 2H), 3.2 (m, 2H),2.79/2.37 (2m, 2H), 2.69/2.27 (2m, 2H), 1.95/1.7 (2m, 2H), 1.8/1.7 (2m,2H), 1.39 (s, 18H), 1.33 (s, 9H), 1.27 (m, 2H), 1.19 (t, 3H), 0.61/0.48(2m, 2H)

Example 131:3-(4-Aminobutyl)-1-[[2-[4-chloro-3-(trifluoromethyl)phenyl]phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 131 is obtained starting from intermediate 118 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.76 (sl, 1H), 7.71 (d, 1H), 7.63 (m, 1H),7.54 (dl, 1H), 7.54 (m, 2H), 7.38 (m, 1H), 4.31 (AB, 2H), 3.46/3.08 (2m,2H), 3.13/2.83 (2m, 2H), 2.92 (m, 2H), 2.11/1.64 (2m, 2H), 1.83/1.34(2m, 2H), 1.57 (m, 2H), 1.06 (m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −62.3

ESI/FIA/HR and MS/MS: [M+H]+=519.1442 (519.1427)

Elemental analysis: C=53.40 (53.24); H=4.76 (5.24); N=5.43 (5.40)

Intermediate 119: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(3-chlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 119 is obtained starting from intermediates 21 and 213 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (t, 1H), 7.45 (m, 3H), 7.4/7.37(2td, 2H), 7.33 (dt, 1H), 7.25 (dd, 1H), 3.94 (m, 2H), 3.53/3.32 (AB,2H), 3.25 (m, 2H), 2.76/2.37 (2m, 2H), 2.7/2.25 (2m, 2H), 1.95/1.78 (2m,2H), 1.82/1.75 (2m, 2H), 1.41 (s, 18H), 1.33 (s, 9H), 1.33 (m, 2H), 1.18(t, 3H), 0.66/0.57 (2m, 2H)

Example 132:3-(4-Aminobutyl)-1-[[2-(3-chlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 132 is obtained starting from intermediate 119 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6 (m, 1H), 7.52 (m, 2H), 7.5-7.35 (m,4H), 7.26 (m, 1H), 4.33 (AB, 2H), 3.41/3.09 (2m, 2H), 3.16/2.81 (2m,2H), 2.92 (m, 2H), 2.09/1.64 (2m, 2H), 1.83/1.34 (2m, 2H), 1.56 (m, 2H),1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.1556 (451.1553)

Elemental analysis: C=58.91 (58.60); H=5.83 (6.26); N=6.32 (6.21)

Intermediate 120: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(4-methylphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 120 is obtained starting from intermediates 21 and 288 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1H), 7.33 (2*m, 2H), 7.23(2*d, 4H), 7.18 (dd, 1H), 3.92 (m, 2H), 3.54/3.35 (2*d, 2H), 3.3 (m,2H), 2.74/2.2 (2*m, 2H), 2.74/2.32 (2*m, 2H), 2.36 (s, 3H), 1.95-1.75(m, 2H), 1.95-1.75 (m, 2H), 1.41/1.33 (2*s, 27H), 1.38 (m, 2H), 1.17 (t,3H), 0.71 (m, 2H)

Example 133:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(4-methylphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 133 is obtained starting from intermediate 120 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (dd, 1H), 7.52/7.5 (2*m, 2H), 7.39 (dd,1H), 7.35 (d, 2H), 7.25 (d, 2H), 4.43/4.28 (2*d, 2H), 3.36/3.1 (2*dd,2H), 3.22/2.83 (2*dd, 2H), 2.94 (m, 2H), 2.38 (s, 3H), 2.09/1.64 (2*m,2H), 1.86/1.6 (2*m, 2H), 1.6/1.35 (2*m, 2H), 1.15/1.05 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=431.2103 (431.2099)

Elemental analysis: C=64.12 (64.17); H=7.45 (7.26); N=6.50 (6.51)

Intermediate 121: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(2,4-dichlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 121 is obtained starting from intermediates 21 and 251 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.73 (m, 1H), 7.51 (m, 1H), 7.51 (m,1H), 7.42/7.35 (m, 2H), 7.31 (m, 1H), 7.12 (m, 1H), 3.92 (m, 2H),3.5-3.2 (m, 2H), 3.5-3.2 (m, 2H), 2.68/2.12 (m, 2H), 2.68/2.35 (m, 2H),1.81 (m, 2H), 1.81 (m, 2H), 1.42 (2*s, 18H), 1.38 (m, 2H), 1.35 (2*s,9H), 1.17 (2*t, 3H), 0.74 (m, 2H)

Example 134:3-(4-Aminobutyl)-1-[[2-(2,4-dichlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 134 is obtained starting from intermediate 121 in accordancewith procedure D described hereinbefore.

¹H NMR: (400/500 MHz, D2O) δ ppm 7.7-7.63 (m, 2H), 7.6-7.5 (m, 2H), 7.46(dd, 1H), 7.33 (m, 1H), 7.3/7.28 (2*d, 1H), 4.42/4.19/3.99 (m, 2H),3.64/3.41/3.14 (m, 2H), 3.38/3.12/2.99/2.84 (m, 2H), 2.95 (m, 2H),2.14/1.67 (m, 2H), 1.9/1.4 (m, 2H), 1.58 (m, 2H), 1.19/1.11 (m, 2H)

¹³C NMR: (400/500 MHz, D2O) δ ppm 132.1, 130.6, 129.5, 127.3, 57, 57,51.8, 38.6, 27, 26.4, 24.5, 20

ESI/FIA/HR and MS/MS: [M+H]+=485.1166 (485.1163)

Elemental analysis: C=54.26 (54.44); H=5.33 (5.61); N=5.83 (5.77)

Intermediate 122: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(2-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 122 is obtained starting from intermediates 21 and 282 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.5 (d, 1H), 7.4-7.2 (m, 2H), 7.4-7.2(m, 1H), 7.09 (m, 1H), 7.09 (m, 2H), 7.01 (t, 1H), 3.96 (m, 2H), 3.7 (s,3H), 3.42 (m, 2H), 3.34 (dd, 2H), 2.73/2.23 (m, 2H), 2.73/2.46 (m, 2H),2-1.7 (m, 2H), 2-1.7 (m, 2H), 1.47 (s, 18H), 1.42 (m, 2H), 1.4 (s, 9H),1.21 (t, 3H), 0.96 (m, 2H)

Example 135:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(2-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 135 is obtained starting from intermediate 122 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7-7.1 (m, 4H), 7.7-7.1 (m, 4H), 4.4-3.9(m, 2H), 3.74 (s, 3H), 3.7-3 (m, 2H), 3.25-2.65 (m, 2H), 2.94 (m, 2H),2.3-1.3 (m, 2H), 2.3-1.3 (m, 2H), 1.61 (m, 2H), 1.3-0.9 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=447.2031 (447.2048)

Elemental analysis: C=62.34 (61.87); H=6.65 (7.00); N=6.46 (6.27)

Intermediate 123: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(3-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 123 is obtained starting from intermediates 21 and 281 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (d, 1H), 7.35 (m, 2H), 7.35 (m,1H), 7.21 (d, 1H), 6.95 (dd, 1H), 6.89 (d, 1H), 6.86 (sl, 1H), 3.93 (m,2H), 3.79 (s, 3H), 3.55/3.37 (2*d, 2H), 3.29 (m, 2H), 2.74/2.21 (m, 2H),2.74/2.33 (m, 2H), 2-1.7 (m, 2H), 2-1.7 (m, 2H), 1.41 (s, 18H), 1.37 (m,2H), 1.33 (s, 9H), 1.17 (t, 3H), 0.68 (m, 2H)

Example 136:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(3-methoxyphenyl)phenyl]-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 136 is obtained starting from intermediate 123 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (m, 1H), 7.53 (m, 2H), 7.46 (t, 1H),7.4 (m, 1H), 7.07 (dd, 1H), 6.95 (m, 2H), 4.43/4.28 (2*d, 2H), 3.84 (s,3H), 3.38/3.1 (m, 2H), 3.2/2.85 (m, 2H), 2.94 (m, 2H), 2.1/1.64 (m, 2H),1.86/1.36 (m, 2H), 1.59 (m, 2H), 1.13/1.06 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=447.2064 (447.2048)

Elemental analysis: C=61.90 (61.87); H=6.25 (7.00); N=6.35 (6.27)

Intermediate 124: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[[2-(4-propan-2-ylphenyl)phenyl]methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 124 is obtained starting from intermediates 21 and 289 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1H), 7.33 (2*m, 2H), 7.31 (d,2H), 7.27 (d, 2H), 7.21 (dd, 1H), 3.93 (m, 2H), 3.6/3.35 (2*d, 2H), 3.33(m, 2H), 2.95 (hept., 1H), 2.73/2.23 (2*m, 2H), 2.73/2.34 (2*m, 2H),1.9-1.75 (m, 2H), 1.9-1.75 (m, 2H), 1.41/1.32 (2*s, 27H), 1.38 (m, 2H),1.25 (d, 6H), 1.18 (t, 3H), 0.7 (m, 2H)

Example 137:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-(4-propan-2-ylphenyl)-phenyl]methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 137 is obtained starting from intermediate 124 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.61 (dd, 1H), 7.52 (2*t, 2H), 7.43 (d,2H), 7.38 (dd, 1H), 7.29 (d, 2H), 4.42/4.24 (2*d, 2H), 3.35/3.11 (2*m,2H), 3.22/2.83 (2*m, 2H), 2.97 (m, 1H), 2.95 (m, 2H), 2.09/1.67 (2*m,2H), 1.85/1.6 (2*m, 2H), 1.6/1.35 (2*m, 2H), 1.24 (d, 6H), 1.15/1.05(2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=459.2418 (459.2412)

Elemental analysis: C=65.54 (65.49); H=7.39 (7.69); N=6.12 (6.11)

Intermediate 125: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-(1H-indazol-4-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 125 is obtained starting from intermediate 21 and1H-indazol-4-carbaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 13.01 (s, 1H), 8.19 (s, 1H), 7.44 (d,1H), 7.27 (dd, 1H), 6.99 (d, 1H), 3.98 (m, 2H), 3.93/3.71 (2*d, 2H),3.29/3.16 (m, 2H), 3.03/2.37 (m, 2H), 2.83/2.52 (m, 2H), 2-1.7 (m, 2H),2-1.7 (m, 2H), 1.38 (s, 18H), 1.33 (s, 9H), 1.24/1.1 (m, 2H), 1.21 (t,3H), 0.65/0.51 (m, 2H)

Example 138:3-(4-Aminobutyl)-4-hydroxy-1-(1H-indazol-4-ylmethyl)-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 138 is obtained starting from intermediate 125 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 8.29 (s, 1H), 7.71 (dl, 1H), 7.49 (dd, 1H),7.3 (dl, 1H), 4.65 (AB, 2H), 3.71/3.39 (2m, 2H), 3.56/3.21 (2m, 2H),2.87 (m, 2H), 2.19/1.74 (2m, 2H), 1.91/1.45 (2m, 2H), 1.54 (quint., 2H),1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=381.1707 (381.1691)

Elemental analysis: C=53.52 (53.68); H=6.73 (6.62); N=14.77 (14.73)

Intermediate 126: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[3-(4-chlorophenyl)pyridin-4-yl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 126 is obtained starting from intermediate 21 and3-(4-chlorophenyl)pyridine-4-carbaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.57 (d, 1H), 8.42 (s, 1H), 7.56 (d,2H), 7.54 (d, 1H), 7.44 (d, 2H), 3.94 (m, 2H), 3.53 (AB, 2H), 3.36 (m,2H), 2.7/2.45 (2m, 2H), 2.7/2.26 (2m, 2H), 1.89 (m, 4H), 1.41 (s, 18H),1.41 (m, 2H), 1.35 (s, 9H), 1.17 (t, 3H), 0.78 (m, 2H)

Example 139:3-(4-Aminobutyl)-1-[[3-(4-chlorophenyl)pyridin-4-yl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 139 is obtained starting from intermediate 126 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.62 (d, 1H), 8.54 (s, 1H), 7.67 (d, 1H),7.58 (d, 2H), 7.38 (d, 2H), 4.46/4.35 (2*d, 2H), 3.47/3.12 (2*m, 2H),3.17/2.95 (2*m, 2H), 2.95 (m, 2H), 2.15/1.68 (2*m, 2H), 1.87/1.61 (2*m,2H), 1.59/1.38 (2*m, 2H), 1.08 (m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 25.1

¹³C NMR: (400 MHz, D2O) δ ppm 147.4, 146.1, 128.3, 126.4, 122.2, 55,53.2, 49.9, 36, 24.3, 23.9, 22.1, 17.3

ESI/FIA/HR and MS/MS: [M+H]+=452.1516 (452.1505)

Elemental analysis: C=55.97 (55.82); H=5.86 (6.02); N=9.28 (9.30)

Intermediate 127: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(3-phenyl-1-benzothiophen-2-yl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 127 is obtained starting from intermediates 21 and 283 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.95 (m, 1H), 7.55 (t, 2H), 7.47 (t,1H), 7.45-7.3 (m, 3H), 7.45-7.3 (m, 2H), 4.05 (m, 2H), 3.81 (dd, 2H),3.42/3.33 (m, 2H), 2.88/2.53 (m, 2H), 2.88/2.7 (m, 2H), 2-1.7 (m, 2H),2-1.7 (m, 2H), 1.49 (m, 2H), 1.39 (s, 27H), 1.23 (t, 3H), 1.14/1.02 (m,2H)

Example 140:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(3-phenyl-1-benzothiophen-2-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 140 is obtained starting from intermediate 127 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.97 (d, 1H), 7.56 (m, 3H), 7.49 (d, 1H),7.45 (t, 1H), 7.35 (m, 1H), 7.35 (m, 2H), 4.6/4.51 (dd, 2H), 3.55/3.18(m, 2H), 3.26/2.9 (m, 2H), 2.9 (m, 2H), 2.18/1.68 (m, 2H), 1.86/1.34 (m,2H), 1.56 (m, 2H), 1.04 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=473.1669 (473.1663)

Elemental analysis: C=61.52 (61.00); H=5.76 (6.19); N=5.51 (5.93);S=6.56 (6.79)

Example 141:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(3-phenylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 141 is obtained starting from intermediate 21 and3-phenylbenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.79-7.4 (m, 9H), 4.49 (m, 1H), 4.29 (d,1H), 3.76 (m, 1H), 3.51 (dd, 1H), 3.39 (m, 1H), 3.13 (dd, 1H), 2.89 (m,2H), 2.27 (m, 1H), 1.92 (m, 1H), 1.79 (m, 1H), 1.58 (unresolved peak,2H), 1.48 (m, 1H), 1.21 (m, 1H), 1.09 (m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=417.1937 (417.1943)

Elemental analysis: C=64.07 (63.45); H=6.72 (7.02); N=6.86 (6.73)

Example 142:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(4-phenylbutyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 142 is obtained starting from intermediate 21 and4-phenylbutanal in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.29 (t, 2H), 7.21 (d, 2H), 7.19 (t, 1H),3.5 (m, 1H), 3.41 (dd, 1H), 3.2 (m, 1H), 3.07 (m, 2H), 3 (m, 1H), 2.92(m, 1H), 2.61 (m, 2H), 2.19 (m, 1H), 1.9 (m, 1H), 1.75-1.1 (m, 10H)

ESI/FIA/HR and MS/MS: [M+H]+=383.2092 (383.2099)

Elemental analysis: C=59.51 (59.67); H=8.12 (8.17); N=7.34 (7.33)

Example 143:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-(5-phenylpentyl)-1,4-azaphosphinane-3-carboxylicAcid

Example 143 is obtained starting from intermediate 21 and5-phenylpentanal in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.33 (t, 2H), 7.26 (d, 1H), 7.21 (t, 1H),3.6 (m, 1H), 3.52 (dd, 1H), 3.28 (m, 1H), 3.1 (m, 3H), 2.99 (m, 2H),2.62 (t, 2H), 2.22 (m, 1H), 1.98 (m, 1H), 1.8-1.6 (unresolved peak, 2H),1.8-1.15 (m, 10H)

ESI/FIA/HR and MS/MS: [M+H]+=397.2251 (397.2256)

Elemental analysis: C=61.01 (60.59); H=7.98 (8.39); N=7.12 (7.07)

Example 145:3-(4-Aminobutyl)-4-hydroxy-1-[(4-methylsulphanylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 145 is obtained starting from intermediate 21 and4-formylthioanisole in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.41/7.37 (2*d, 4H), 4.38/4.17 (2*d, 2H),3.7/3.31 (2*m, 2H), 3.45/3.09 (2*m, 2H), 2.92 (m, 2H), 2.49 (s, 3H),2.22/1.78 (2*m, 2H), 1.92/1.59 (2*m, 2H), 1.58/1.47 (2*m, 2H), 1.22/1.1(2*m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 25.9

ESI/FIA/HR and MS/MS: [M+H]+=387.1512 (387.1507)

Elemental analysis: C=52.52 (52.84); H=6.70 (7.04); N=7.35 (7.25);S=8.34 (8.30)

Example 146:3-(4-Aminobutyl)-1-[(3-carboxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 146 is obtained starting from intermediate 21 and methyl3-formylbenzoate in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.03 (2*m, 2H), 7.7 (d, 1H), 7.59 (t, 1H),4.52/4.3 (2*d, 2H), 3.75/3.4 (2*m, 2H), 3.4/3.12 (2*m, 2H), 2.9 (m, 2H),2.25/1.81 (2*m, 2H), 1.95/1.58 (2*m, 2H), 1.62-1.43 (unresolved peak,2H), 1.2/1.1 (2*m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 25

ESI/FIA/HR and MS/MS: [M+H]+=385.1522 (385.1528)

Elemental analysis: C=53.60 (53.12); H=6.54 (6.56); N=7.42 (7.29)

Example 147:3-(4-Aminobutyl)-1-[(4-carboxyphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 147 is obtained starting from intermediate 21 and methyl4-formylbenzoate in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8 (d, 2H), 7.6 (d, 2H), 4.52/4.3 (2*d, 2H),3.75/3.4 (2*m, 2H), 3.45/3.13 (dd, 2H), 2.9 (m, 2H), 2.28/1.8 (2*m, 2H),1.9/1.55 (2*m, 2H), 1.55/1.5 (m, 2H), 1.2/1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=385.1524 (385.1528)

Elemental analysis: C=52.66 (53.12); H=6.04 (6.56); N=7.33 (7.29)

Example 148:3-(4-Aminobutyl)-1-[[4-(difluoromethoxy)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 148 is obtained starting from intermediate 21 and4-(difluoromethoxy)benzaldehyde in accordance with procedures F and Ddescribed hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5 (d, 2H), 7.25 (d, 2H), 6.83 (t, 1H),4.4/4.22 (2*d, 2H), 3.7/3.32 (dd, 2H), 3.45/3.1 (dd, 2H), 2.92 (m, 2H),2.25/1.78 (2*m, 2H), 1.9/1.6 (2*m, 2H), 1.6/1.46 (2*m, 2H), 1.22/1.1(2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=407.1551 (407.1547)

Elemental analysis: C=50.33 (50.25); H=5.97 (6.20); N=7.02 (6.89)

Example 149:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(1S)-1-phenylethyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 149 is obtained starting from intermediate 21 and acetophenonein accordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5 (m, 5H), 4.67 (quad., 1H), 3.72/3.53(2*m, 1H), 3.62/3.41 (2*m, 1H), 3.29/3.13 (2*m, 1H), 3.09-2.9 (m, 1H),3.09-2.9 (m, 2H), 2.28/2.11 (2*m, 1H), 2-1.65 (m, 1H), 2-1.65 (m, 2H),1.7 (2*d, 3H), 1.7-1.05 (m, 2H), 1.7-1.05 (m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 26.4/26.2

ESI/FIA/HR and MS/MS: [M+H]+=355.1807 (355.1781)

Elemental analysis: C=57.43 (57.62); H=7.57 (7.68); N=7.96 (7.99)

Example 150:3-(4-Aminobutyl)-1-[(3,4-difluorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 150 is obtained starting from intermediate 21 and3,4-difluorobenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.46-7.22 (m, 3H), 4.28 (AB, 2H), 3.69/3.42(2m, 2H), 3.34/3.1 (m+dd, 2H), 2.92 (m, 2H), 2.23/1.77 (2m, 2H),1.92/1.46 (2m, 2H), 1.59 (quint., 2H), 1.22/1.09 (2m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −135.5

³¹P NMR: (300 MHz, D2O) δ ppm 23

ESI/FIA/HR and MS/MS: [M+H]+=377.1416 (377.1441)

Elemental analysis: C=50.40 (51.06); H=6.20 (6.16); N=7.38 (7.44)

Example 151:3-(4-Aminobutyl)-1-[[3-[dimethylamino)methyl]-4-hydroxyphenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 151 is obtained starting from intermediate 21 and3-(dimethylaminomethyl)-4-hydroxy-benzaldehyde in accordance withprocedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.45 (d, 1H), 7.43 (s, 1H), 7.02 (d, 1H),4.35/4.18 (2*d, 2H), 432/4.28 (2*d, 2H), 3.7/3.3 (2*m, 2H), 3.44/3.08(dd, 2H), 2.9 (m, 2H), 2.8 (d, 6H), 2.2/1.75 (2*m, 2H), 1.9/1.45 (2*m,2H), 1.6 (m, 2H), 1.25/1.1 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=414.2155 (414.2157)

Elemental analysis: C=46.97 (47.82); H=5.90 (6.31); N=7.67 (7.97)

Example 152:3-(4-Aminobutyl)-1-[(2-fluorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 152 is obtained starting from intermediate 21 and2-fluorobenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.5 (m, 2H), 7.26 (m, 2H), 4.41 (sl, 2H),3.7/3.35 (2m, 2H), 3.52/3.21 (2m, 2H), 2.94 (m, 2H), 2.22/1.77 (2m, 2H),1.95/1.49 (2m, 2H), 1.61 (quint., 2H), 1.28/1.14 (2m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −115

³¹P NMR: (300 MHz, D2O) δ ppm 25.6

ESI/FIA/HR and MS/MS: [M+H]+=359.1530 (359.1535).

Elemental analysis: C=53.34 (53.63); H=6.46 (6.75); N=7.77 (7.82)

Example 153:3-(4-Aminobutyl)-1-[(3-fluorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 153 is obtained starting from intermediate 21 and3-fluorobenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.48 (m, 1H), 7.24 (m, 3H), 4.31 (AB, 2H),3.71/3.35 (2m, 2H), 3.45/3.12 (2m, 2H), 2.92 (m, 2H), 2.24/1.77 (2m,2H), 1.93/1.46 (2m, 2H), 1.58 (quint., 2H), 1.22/1.1 (2m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −112

³¹P NMR: (300 MHz, D2O) δ ppm 22.9

ESI/FIA/HR and MS/MS: [M+H]+=359.1536 (359.1535)

Elemental analysis: C=53.15 (53.63); H=6.41 (6.75); N=7.83 (7.82)

Example 154:3-(4-Aminobutyl)-1-[(6-aminopyridin-3-yl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 154 is obtained starting from intermediate 21 and2-(Boc-amino)pyridine-5-carboxaldehyde in accordance with procedures Fand D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.97 (d, 1H), 7.61 (dd, 1H), 6.71 (d, 1H),4.18 (AB, 2H), 3.67/3.29 (2m, 2H), 3.42/3.05 (2m, 2H), 2.93 (m, 2H),2.22/137 (2m, 2H), 1.93/1.47 (2m, 2H), 1.59 (quint, 2H), 1.25/1.11 (2m,2H)

³¹P NMR: (400 MHz, D2O) δ ppm 23.2

ESI/FIA/HR and MS/MS: [M+H]+=357.1696 (357.1691)

Elemental analysis: C=51.09 (50.56); H=6.51 (7.07); N=15.78 (15.72)

Example 155:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-phenoxyphenyl)-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 155 is obtained starting from intermediate 21 and2-phenoxybenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.47 (t, 1H), 7.41 (t, 2H), 7.27-7.09 (m,4H), 7.05 (d, 2H), 4.27 (AB, 2H), 3.68/3.3 (2m, 2H), 3.46/3.07 (2m, 2H),2.91 (m, 2H), 2.23/1.76 (2m, 2H), 1.93/1.46 (2m, 2H), 1.6 (quint., 2H),1.15 (m, 2H)

³¹P NMR: (300 MHz, D2O) δ ppm 25.8

ESI/FIA/HR and MS/MS: [M+H]+=433.1894 (433.1892)

Elemental analysis: C=61.51 (61.10); H=6.57 (6.76); N=6.61 (6.48)

Example 156:3-(4-Aminobutyl)-1-[[2-(4-chlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 156 is obtained starting from intermediate 21 and2-(4-chlorophenyl)benzaldehyde in accordance with procedures F and Ddescribed hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6/7.52/7.4 (m, 3H), 7.52/7.34 (2d, 4H),4.35 (AB, 2H), 3.4/3.1 (2m, 2H), 3.17/2.86 (2m, 2H), 2.94 (m, 2H),2.09/1.64 (2m, 2H), 1:85/1.35 (2m, 2H), 1.58 (m, 2H), 1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.1559 (451.1553)

Elemental analysis: C=58.24 (58.60); H=5.82 (6.26); N=6.48 (6.21)

Example 157:3-(4-Aminobutyl)-1-[(2-bromophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 157 is obtained starting from intermediate 21 and2-bromobenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.75 (dl, 1H), 7.53 (dd, 1H), 7.45 (tl,1H), 7.39 (td, 1H), 4.44 (AB, 2H), 3.74/3.43 (2m, 2H), 3.5/3.28 (2m,2H), 2.94 (m, 2H), 2.24/1.79 (2m, 2H), 1.95/1.5 (2m, 2H), 1.6 (m, 2H),1.26/1.1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=419.0732 (419.0735)

Elemental analysis: C=45.33 (45.84); H=5.29 (5.77); N=7.00 (6.68)

Example 159:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-oxo-1,3-dihydroindol-5-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 159 is obtained starting from intermediate 21 andoxindole-5-carboxaldehyde in accordance with procedures F and Ddescribed hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.35 (d, 1H), 7.3 (dd, 1H), 7 (d, 1H),4.35/4.15 (dd, 2H), 3.7/3.3 (2m, 2H), 3.6 (dd, 2H), 3.4/3.1 (2dd, 2H),2.9 (m, 2H), 2.2/1.75 (2m, 2H), 1.9/1.45 (2m, 2H), 1.58 (m, 2H), 1.3-1(2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=396.1692 (396.1688)

Elemental analysis: C=54.70 (54.68); H=6.42 (6.63); N=10.57 (10.63)

Example 160:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 160 is obtained starting from intermediate 21 and2-(3-methyl-1,2,4-oxadiazol-5-yl)benzaldehyde in accordance withprocedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.26 (d, 1H), 7.72 (m, 2H), 7.65 (d, 1H),4.78/4.36 (2*d, 2H), 4/3.55 (m, 2H), 3.44/3.25 (m, 2H), 2.91 (m, 2H),2.5 (s, 3H), 2.31/1.88 (m, 2H), 1.88/1.49 (m, 2H), 1.58 (m, 2H),1.22/1.02 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=423.1801 (423.1797)

Elemental analysis: C=53.57 (54.02); H=6.25 (6.44); N=12.77 (13.26)

Example 161:3-(4-Aminobutyl)-4-hydroxy-1-[[2-[2-methyl-5-(trifluoromethyl)-pyrazol-3-yl]phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 156 is obtained starting from intermediate 21 and2-[1-methyl-3(trifluoromethyl)-1H-pyrazol-5-yl]benzaldehyde inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.71 (d, 1H), 7.67 (t, 1H), 7.63 (t, 1H),7.48 (d, 1H), 6.83 (s, 1H), 4.3/4.18 (dl, 2H), 3.53/3.21 (m, 2H), 3.27(s, 3H), 3.27/3.03 (m, 2H), 2.94 (m, 2H), 2.18/1.71 (m, 2H), 2.18/1.43(m, 2H), 1.6 (m, 2H), 1.18/1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=489.1903 (489.1878)

Elemental analysis: C=51.66 (51.64); H=5.61 (5.78); N=11.25 (11.47)

Example 162:3-(4-Aminobutyl)-1-[[2-(2,4-difluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 162 is obtained starting from intermediates 21 and 287 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.65 (m, 1H), 7.57 (m, 2H), 7.4 (m, 1H),7.34 (m, 1H), 7.1 (2*m, 2H), 4.45-4 (m, 2H), 3.7-2.8 (m, 2H), 3.7-2.8(m, 2H), 2.93 (m, 2H), 2.15/1.66 (2*m, 2H), 1.88/1.6 (2*m, 2H), 1.6/1.38(2*m, 2H), 1.15/1.05 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=453.1745 (453.1754)

Elemental analysis: C=58.27 (58.40); H=6.09 (6.01); N=6.17 (6.19)

Example 163:3-(4-Aminobutyl)-1-{[2-fluoro-6-(4-hydroxyphenyl)phenyl]-methyl}-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 163 is obtained starting from intermediate 21 and2-fluoro-6-(4-hydroxyphenyl)benzaldehyde in accordance with procedures Fand D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.52 (m, 1H), 7.27 (m, 1H), 7.22 (d, 2H),7.19 (m, 1H), 6.98 (d, 2H), 4.41 (dd, 2H), 3.45/3.09 (m, 2H), 3.16/2.9(m, 2H), 2.94 (m, 2H), 2.09/1.64 (m, 2H), 1.86/1.35 (m, 2H), 1.59 (m,2H), 1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.1813 (451.1798)

Elemental analysis: C=58.33 (58.66); H=5.35 (6.27); N=6.49 (6.22)

Example 164:3-(4-Aminobutyl)-1-{[2-(1,3-benzodioxol-5-yl)phenyl]methyl}-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 164 is obtained starting from intermediates 21 and 279 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.2-7.9 (s, 3H), 7.45 (d, 1H), 7.3 (m,2H), 7.15 (d, 1H), 6.95 (dd, 1H), 6.95 (s, 1H), 6.8 (dd, 1H), 6.05 (s,2H), 3.5 (d, 1H), 3.4 (d, 1H), 2.9 (m, 1H), 2.7 (t, 2H), 2.55 (m, 1H),2.35 (m, 1H), 2.25 (m, 1H), 1.7 (m, 1H), 1.6-1 (m, 7H)

ESI/FIA/HR and MS/MS: [M+H]+=461.1854 (461.1841)

Elemental analysis: C=60.04 (59.99); H=6.06 (6.35); N=5.62 (6.08)

Example 165:3-(4-Aminobutyl)-4-hydroxy-1-[{2-(6-methoxypyridin-3-yl)phenyl]-methyl}-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 165 is obtained starting from intermediate 21 and2-(6-methoxy-3-pyridinyl)benzaldehyde in accordance with procedures Fand D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 8.05 (s, 1H), 7.75 (dd, 1H), 7.6 (m, 1H),7.5 (m, 2H), 7.35 (m, 1H), 6.95 (d, 1H), 4.4 (d, 1H), 4.25 (d, 1H), 3.9(s, 3H), 3.55-3.3 (m, 1H), 3.3-3.1 (m, 1H), 3.1 (m, 1H), 2.95 (t, 2H),2.85 (m, 1H), 2.1 (m, 1H), 1.85 (m, 1H), 1.75-1.5 (m, 3H), 1.35 (m, 1H),1.2-0.95 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=448.1996 (448.2001)

Elemental analysis: C=59.45 (59.05); H=6.75 (6.76); N=9.12 (9.39)

Example 166:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[{2-(6-oxo-1H-pyridin-3-yl)phenyl]methyl}-1,4-azaphosphinane-3-carboxylicAcid

Example 166 is obtained starting from intermediates 21 and 237 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300/400 MHz, D2O) δ ppm 7.7 (dd, 1H), 7.6 (s, 1H), 7.6-7.3(2*m, 2H), 6.7 (d, 1H), 4.35 (m, 2H), 3.6-3.4 (m, 1H), 3.4-3.05 (m, 2H),3 (m, 1H), 2.9 (t, 2H), 2.1 (m, 1H), 1.85 (m, 1H), 1.7 (m, 1H), 1.6 (m,2H), 1.4 (m, 1H), 1.25-0.95 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=434.1860 (434.1844)

Elemental analysis: C=58.86 (58.19); H=6.27 (6.51); N=9.89 (9.69)

Example 167:3-(4-Aminobutyl)-4-hydroxy-1-[(2-imidazol[2-a]pyridin-3-ylphenyl)-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 167 is obtained starting from intermediates 21 and 227 inaccordance with procedures F and D, described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.98 (d, 1H), 7.68 (s, 1H), 7.65 (d, 1H),7.65 (m, 2H), 7.52 (m, 1H), 7.45 (dd, 1H), 7.22 (m, 1H), 6.98 (t, 1H),4.25 (m, 2H), 3.45/3.1 (2*m, 2H), 2.9 (m, 2H), 2.85 (m, 2H), 2.12/1.55(2*m, 2H), 1.8/1.55 (2*m, 2H), 1.55/0.95 (2*m, 2H), 1.28/0.95 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=457.2004 (457.20046)

Elemental analysis: C=59.82 (60.52); H=5.48 (6.40); N=11.98 (12.27)

Example 168:3-(4-Aminobutyl)-1-[(2-chlorophenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 168 is obtained starting from intermediate 21 and2-chlorobenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.58/7.53 (2*d, 2H), 7.48/7.4 (2*m, 2H),4.44 (m, 2H), 3.71/3.41 (2*m, 2H), 3.51/128 (2*m, 2H), 2.94 (m, 2H),2.22/1.78 (2*m, 2H), 1.95/1.61 (2*m, 2H), 1.6/1.49 (2*m, 2H), 1.28/1.11(2*m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm −25.5

ESI/FIA/HR and MS/MS: [M+H]+=375.1235 (375.1240)

Elemental analysis: C=51.58 (51.27); H=6.22 (6.45); N=7.65 (7.47)

Example 169:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(1R)-1-phenylethyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 169 is obtained starting from intermediate 21 and acetophenonein accordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.5 (m, 5H), 4.67 (quad., 1H), 3.72/3.53(2*m, 1H), 3.62/3.41 (2*m, 1H), 3.29/3.13 (2*m, 1H), 3.09-2.9 (m, 1H),3.09-2.9 (m, 2H), 2.28/2.11 (2*m, 1H), 2-1.65 (in, 1H), 2-1.65 (m, 2H),1.7 (2*d, 3H), 1.7-1.05 (m, 2H), 1.7-1.05 (m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 26.4/26.2

ESI/FIA/HR and MS/MS: [M+H]+=355.1783 (355.1786)

Elemental analysis: C=58.22 (57.62); H=7.85 (7.68); N=8.04 (7.90)

Example 170:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-phenylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 170 is obtained starting from intermediate 21 and2-phenylbenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.65-7.3 (m, 6H), 4.33 (AB, 2H), 3.43-3(m, 3H), 2.92 (dd, 1H), 2.82 (m, 2H), 2.06/1.57 (2m, 2H), 1.83/1.33 (2m,2H), 1.57 (m, 2H), 1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=417.1945 (417.1943)

Elemental analysis: C=63.68 (63.45); H=6.84 (7.02); N=6.85 (6.73)

Example 171:3-(4-Aminobutyl)-1-{[2-(furan-3-yl)phenyl]methyl}-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 171 is obtained starting from intermediates 21 and 290 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.68 (m, 1H), 7.65 (m, 1H), 7.58-7.44 (m,4H), 6.63 (m, 1H), 4.49/4.4 (2*d, 2H), 3.5/3.22 (2*m, 2H), 3.34/3.01(2*m, 2H), 2.94 (m, 2H), 2.1/1.68 (2*m, 2H), 1.69/1.6 (2*m, 2m),1.59/1.41 (2*m, 2H), 1.18/1.08 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=407.1736 (407.1735)

Elemental analysis: C=59.20 (59.11); H=7.12 (6.70); N=7.00 (6.89)

Example 172:3-(4-Aminobutyl)-4-hydroxy-1-[[2-(3-hydroxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 172 is obtained starting from intermediates 21 and 281 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.52 (m, 2H), 7.39 (m, 1H), 7.39 (m, 1H),7.29 (d, 1H), 6.95 (dd, 1H), 6.9 (dl, 1H), 6.85 (sl, 1H), 4.44/4.29 (d,2H), 3.38/3.13 (m, 2H), 3.2/2.85 (m, 2H), 3.13/1.36 (m, 2H), 2.94 (m,2H), 2.1-1.65 (m, 2H), 1.59 (m, 2H), 1.13/1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=433.1895 (433.1892)

Elemental analysis: C=61.64 (61.10); H=6.51 (6.76); N=6.73 (6.48)

Example 173:3-(4-Aminobutyl)-1-[[2-(4-chlorophenyl)-4-fluorophenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 173 is obtained starting from intermediates 21 and 220 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.59 (dd, 1H), 7.51 (d, 2H), 7.32 (d, 2H),7.23 (td, 1H), 7.14 (dd, 1H), 4.3 (AB, 2H), 3.37/3.06 (2m, 2H),3.11/2.81 (2m, 2H), 2.92 (m, 2H), 2.06/1.62 (2m, 2H), 1.83/1.33 (2m,2H), 1.56 (m, 2H), 1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=469.1470 (469.1459)

Elemental analysis: C=56.07 (56.35); H=5.39 (5.80); N=6.03 (5.97)

Example 174:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-propan-2-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 174 is obtained starting from intermediate 21 and2-isopropylbenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (500 MHz, D2O) δ ppm 7.49 (d, 1H), 7.45 (t, 1H), 7.38 (d, 1H),7.28 (t, 1H), 4.39 (dd, 2H), 3.65 (dd, 1H), 3.5 (dd, 1H), 3.35 (m, 1H),3.21 (dd, 1H), 3.09 (m, 1H), 2.91 (m, 2H), 2.17 (m, 1H), 1.93 (m, 1H),1.74 (m, 1H), 1.58 (m, 2H), 1.47 (m, 1H), 1.24 (m, 1H), 1.2/1.18 (2*s,6H), 1.1 (m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=383.2097 (383.2099)

Elemental analysis: C=59.45 (59.67); H=8.00 (8.17); N=7.60 (7.33)

Example 175:3-(4-Aminobutyl)-1-[[2-(3,4-dichlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 175 is obtained starting from intermediates 21 and 215 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.62 (d, 1H), 7.6 (m, 1H), 7.54 (d, 1H),7.52 (m, 2H), 7.37 (m, 1H), 7.24 (dd, 1H), 4.34 (AB, 2H), 3.45/3.07 (2m,2H), 3.12/2.83 (2m, 2H), 2.93 (m, 2H), 2.1/1.63 (2m, 2H), 1.84/1.33 (2m,2H), 1.57 (m, 2H), 1.04 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=485.1158 (485.1163).

Elemental analysis: C=54.91 (54.44); H=5.37 (5.61); N=5.35 (5.77)

Example 176:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(3-phenylthiophen-2-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 176 is obtained starting from intermediates 21 and 284 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.62 (d, 1H), 7.49 (t, 2H), 7.44 (t, 1H),7.4 (d, 2H), 7.17 (d, 1H), 4.6 (AB, 2H), 3.52/3.13 (2m, 2H), 3.13/2.73(2m, 2H), 2.91 (m, 2H), 2.12/1.66 (2m, 2H), 1.81/1.26 (2m, 2H), 1.55 (m,2H), 0.97 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=423.1525 (423.1507)

Elemental analysis: C=56.76 (56.86); H=6.46 (6.44); N=7.19 (6.63);S=7.30 (7.59)

Procedure G: Chiral Separation of the Diastereoisomers of Intermediate20b Intermediate 128: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-benzyl-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

DMSO (30 mL) and 60% NaH (6.78 g, 186.6 mmol, 1.6 eq) are introduced insuccession under an argon atmosphere into a 1 L three-necked flaskequipped with mechanical stirring. The flask is maintained at ambienttemperature by means of a water bath. A solution of intermediate 204(41.1 g, 116.7 mmol, 1.1 eq) in DMSO (25 mL) is then added dropwise overa period of 5 minutes. A solution of intermediate 19 (37.54 g, 106 mmol)in DMSO (100 mL) is then added dropwise, the temperature beingmaintained below 20° C. The addition in fact causes pronounced heatingas well as pronounced thickening of the reaction mixture. When theaddition is complete, 100 mL of anhydrous THF are then added in orderthat stirring can be maintained. After 3 hours, the reaction mixture iscooled by means of an ice-water bath and hydrolysed by addition of 500mL of a saturated NH₄Cl solution. The mixture is then extracted withAcOEt (3×300 mL). The organic phases are then combined, washed with asaturated NaCl solution (2×300 mL) and dried over MgSO₄, before beingconcentrated under reduced pressure to yield a yellowish solid (69.94g), a mixture of 4 diastereoisomers. The 4 diastereoisomers ofintermediate 20b are separated on a 2.5 kg chiral column of type(R,R)-Whelk-O-1 in batches of 8 g, each batch requiring 2 passes underthe following conditions:

1st Pass:

The mixture containing the 4 diastereoisomers of intermediate 20b (8 gof crude product) is applied to a chiral column of type (R,R)-Whelk-O-1of 2.5 kg using as mobile phase DCM/heptane (55:45)+10% NEt₃ in order toisolate diastereoisomer 4 (number allocated according to the order ofdischarge from the column) of intermediate 20b.

2nd Pass:

The mixture containing the remaining 3 diastereoisomers of intermediate20b is applied to a 2.5 kg chiral column of type (R,R)-Whelk-O-1 usingas mobile phase MTBE+10% DEA in order to isolate diastereoisomer 2.

After 9 injections, the fractions containing diastereoisomers 2 and 4 ofintermediate 20b are then collected and evaporated under reducedpressure to yield intermediate 128 (25.2 g, 40.3 mmol), quaternarycarbon of the (S) configuration with a yield of 38%.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.3 (m, 5H), 4 (m, 2H), 3.6 (d, 1H),3.4 (d, 1H), 3.35 (m, 2H), 2.9 (m, 1H), 2.8 (dd, 1H), 2.45 (dd, 1H), 2.3(m, 1H), 1.9 (m, 4H), 1.4 (m, 2H), 1.38 (s, 18H), 1.35 (s, 9H), 1.2 (t,3H), 0.8 (3, 2H).

IR (cm⁻¹): 1760-1680 cm⁻¹ (C═O), 1124 cm⁻¹ (P═O), 1124 cm⁻¹ (C—O—C).

Intermediate 129: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 128 (30.35 g, 48.6 mol), ethanol (200 mL), Pd/C (3.03 g,10% by mass) and 37% HCl (3 mL, 0.8 eq) are introduced in successioninto a 500 mL flask at ambient temperature and under a stream of argon.The argon is then replaced by a hydrogen atmosphere. The reaction ismonitored by LC/MS. After 4 hours, the reaction is complete and thecatalyst is filtered off over glass fibre. The filtrate is evaporated todryness in order to obtain a yellow oil, which is taken up in AcOEt (200mL) and in a 10% NaHCO₃ solution (200 mL). After decantation, theaqueous phase is extracted with AcOEt (3×100 mL). The organic phases arecombined and then washed with a saturated NaCl solution (400 mL), driedover MgSO₄ and concentrated to yield intermediate 129 in the form of awhite solid (23.12 g, 43.24 mmol) with a yield of 89%.

¹H NMR: (DMSO-d₆, 400 MHz) δ 4.01 to 3.88 (m, 2H), 3.47 (m, 2H),2.95-2.68 (2m, 2H), 2.95 (m, 2H), 2.23 (m, 1H), 1.92-1.68 (m, 4H), 1.48(m, 2H), 1.44 (s, 9H), 1.41 (s, 9H), 1.3 (s, 9H), 1.27/0.97 (2m, 2H),1.24/0.97 (2t, 3H).

IR (cm⁻¹): 1715-1692 cm⁻¹ (C═O), 1125 cm⁻¹ (C—O—C).

Example 177:(3S)-3-(4-Aminobutyl)-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 177 is obtained starting from intermediate 128 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.49 (m, 5H), 4.41/4.21 (2d, 2H), 3.7/3.32(2m, 2H), 3.5/3.1 (2m, 2H), 2.91 (m, 2H), 2.22/1.78 (2m, 2H), 1.92 (m,1H), 1.6 (m, 2H), 1.45 (m, 1H), 1.22/1.1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=341.1638 (341:1630)

Elemental analysis: C=56.43 (56.46); H=7.33 (7.40); N=8.20 (8.23)

RP: −45.630 (589 nm, T=20° C., C=1.1)

Intermediate 131: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-[[2-(3,4-dimethoxyphenyl)-4-fluorophenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 131 is obtained starting from intermediates 129 and 229 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.5 (dd, 1H), 7.15 (m, 1H), 7.05 (m,2H), 6.9 (m, 2H), 3.95 (m, 2H), 3.8 (2s, 6H), 3.55 (d, 1H), 3.35 (d,1H), 3.3 (m, 2H), 2.85-2.65 (m, 2H), 2.35 (dd, 1H), 2.25 (m, 1H), 2-1.75(m, 4H), 1.45-1.3 (m, 2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.2 (t, 3H),0.8-0.6 (m, 2H).

Example 179:(3S)-3-(4-Aminobutyl)-1-[[2-(3,4-dimethoxyphenyl)-4-fluorophenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 179 is obtained starting from intermediate 131 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6 (dd, 1H), 7.2 (td, 1H), 7.1 (m, 1H), 7(dd, 1H), 6.9 (dd, 1H), 4.4/4.25 (2 d, 2H), 3.8 (2 s, 6H), 3.35 (m, 1H),3.2-2.75 (m, 5H), 2.05 (m, 1H), 1.8 (m, 1H), 1.6 (m, 3H), 1.3 (m, 1H), 1(m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=495.2056 (495.2060)

Elemental analysis: C=58.64 (58.29); H=6.44 (6.52); N=5.72 (5.67)

RP: −23.170 (589 nm, T=21° C., C=0.8)

Intermediate 132: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(4-methylphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 132 is obtained starting from intermediates 129 and 272 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.51 (dd, 1H), 7.26 (s, 4H), 7.18 (td,1H), 7.01 (dd, 1H), 3.93 (m, 2H), 3.42 (AB, 2H), 3.34 (m, 2H), 2.72/2.2(2m, 2H), 2.72/2.32 (2m, 2H), 2.36 (s, 3H), 1.9-1.7 (m, 4H), 1.41 (s,18H), 1.37 (m, 2H), 1.34 (s, 9H), 1.17 (t, 3H), 0.7 (m, 2H)

Example 180:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(4-methylphenyl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 180 is obtained starting from intermediate 132 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.61 (dd, 1H), 7.36 (d, 2H), 7.26 (d, 2H),7.23 (td, 1H), 7.15 (dd, 1H), 4.41/4.26 (2*d, 2H), 3.35/3.09 (m, 2H),3.17/2.81 (m, 2H), 2.95 (m, 2H), 2.37 (s, 3H), 2.08/1.64 (m, 2H),1.85/1.35 (m, 2H), 1.6 (m, 2H), 1.13/1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=449.2005 (449.2005)

Elemental analysis: C=61.57 (61.60); H=6.53 (6.74); N=6.45 (6.25)

RP: −15.640 (589 nm, T=20° C., C=1.0)

Intermediate 133: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-phenylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 133 is obtained starting from intermediate 129 and2-phenylbenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.52-7.2 (m, 9H), 4.06-3.86 (m, 2H),3.55/3.36 (AB, 2H), 3.36 (m, 2H), 2.71/2.32/2.19 (3m, 4H), 1.95-1.65 (m,4H), 1.42/1.34 (2s, 27H), 1.37 (m, 2H), 1.21/1.17 (2t, 3H), 0.68 (m, 2H)

Example 181:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-phenylphenyl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 181 is obtained starting from intermediate 133 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.65-7.3 (m, 9H), 4.3 (AB, 2H), 3.43/3(m, 3H), 2.92 (dd, 1H), 2.82 (m, 2H), 2.06-1.57 (2m, 2H), 1.83/1.33 (2m,2H), 1.57 (m, 2H), 1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=417.1938 (417.1943)

Elemental analysis: C=62.99 (63.45); H=6.45 (7.02); N=6.93 (6.73)

Intermediate 134: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-pyrimidin-5-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 134 is obtained starting from intermediates 129 and 236 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 9.2 (s, 1H), 8.85 (s, 2H), 7.45 (m,3H), 7.35 (d, 1H), 3.95 (m, 2H), 3.55 (d, 1H), 3.4 (d, 1H), 3.3 (m, 2H),2.8-2.55 (m, 2H), 2.45-2.15 (2*m, 2H), 2.15-1.7 (m, 2H), 2-1.55 (m, 4H),1.5-1.25 (3s, 27H), 1.2 (t, 3H), 0.6 (m, 2H)

Example 182:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-pyrimidin-5-ylphenyl)-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 182 is obtained starting from intermediate 134 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 9.15 (s, 1H), 8.82 (s, 2H), 7.1-7.55 (in,3H), 7.43 (d, 1H), 4.4/4.3 (2d, 2H), 3.6-3.35 (m, 1H), 3.3-3.1 (m, 1H),3.1 (m, 1H), 2.95 (m, 3H), 2.1 (m, 1H), 1.85 (m, 1H), 1.65 (m, 1H),1.62-1.45 (m, 2H), 1.35 (m, 1H), 1.15-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=419.1855 (419.1848)

Elemental analysis: C=57.01 (57.41); H=6.57 (6.50); N=13.45 (13.39)

RP: −20.520 (589 nm, T=20° C., C=1.0)

Intermediate 135: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-thiophen-2-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 135 is obtained starting from intermediate 129 and2-(2-thienyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.62 (d, 1H), 7.45-4.3 (m, 4H), 7.25(d, 1H), 7.15 (t, 1H), 4.1-3.9 (quad., 2H), 3.65/3.45 (d, 2H), 3.4-3.2(m, 2H), 2.9-2.7 (m, 2H), 2.4-2.3 (m, 2H), 1.9-1.7 (m, 4H), 1.5-1.3 (m,2H), 1.4/1.35 (2*s, 27H), 1.2 (t, 3H), 0.7-0.5 (m, 2H)

Example 183:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-thiophen-2-ylphenyl)-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 183 is obtained starting from intermediate 135 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (d, 1H), 7.55 (d, 1H), 7.48 (m, 2H),7.45 (d, 1H), 7.15 (dd, 1H), 7.1 (t, 1H), 4.5/1.4 (2*d, 2H), 3.5-3.2 (m,3H), 3-2.85 (m, 3H), 2.15/1.7 (m, 4H), 1.88 (m, 1H), 1.55 (m, 2H), 1.2-1(m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=423.1505 (423.1507)

Elemental analysis: C=57.14 (56.86); H=6.12 (6.44); N=6.61 (6.63);S=7.33 (7.59)

RP: −18.340 (589 nm, T=20° C., C=0.9)

Intermediate 136: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-pyridin-3-ylphenyl)methyl]-1,4-azaphosphinane-3-carboxylate

Intermediate 136 is obtained starting from intermediates 129 and 260 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.59 (dd, 1H), 8.56 (dd, 1H), 7.82 (dt,1H), 7.49 (dd, 1H), 7.48 (ddd, 1H), 7.42/7.39 (2td, 2H), 7.27 (dd, 1H),3.92 (m, 2H), 3.44 (AB, 2H), 3.3 (m, 2H), 2.7/2.2 (2m, 2H), 2.7/2.35(2m, 2H), 1.95-1.66 (m, 4H), 1.42 (s, 18H), 1.35 (m, 2H), 1.33 (s, 9H),1.17 (t, 3H), 0.63 (m, 2H)

Example 184:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-pyridin-3-ylphenyl)-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 184 is obtained starting from intermediate 136 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.57 (d, 1H), 8.48 (s, 1H), 7.83 (d,1H), 7.65 (m, 1H), 7.57 (m, 1H), 7.57 (m, 2H), 7.4 (m, 1H), 4.41/4.29(dd, 2H), 3.44/3.12 (dd, 2H), 3.2/2.86 (dd, 2H), 2.93 (m, 2H), 2.1/1.67(2*m, 2H), 1.85/1.35 (2*m, 2H), 1.59 (m, 2H), 1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=418.1871 (418.1895)

Elemental analysis: C=60.35 (60.42); H=6.74 (6.76); N=9.70 (10.07)

RP: −20.940 (589 nm, T=28° C., C=0.9)

Intermediate 137: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(3-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 137 is obtained starting from intermediates 129 and 222 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.51 (dd, 1H), 7.36 (t, 1H), 7.2 (td,1H), 7.05 (dd, 1H), 6.97 (d, 1H), 6.91 (m, 1H), 6.9 (m, 1H), 3.93 (m,2H), 3.79 (s, 3H), 3.52/3.33 (2*d, 2H), 3.33 (m, 2H), 2.72/2.21 (m, 2H),2.72/2.32 (m, 2H), 2-1.75 (m, 4H), 1.4 (s, 18H), 1.37 (m, 2H), 1.34 (s,9H), 1.17 (t, 3H), 0.69 (m, 2H)

Example 185:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(3-methoxyphenyl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 185 is obtained starting from intermediate 137 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.62 (dd, 1H), 7.46 (t, 1H), 7.25 (td, 1H),7.16 (dd, 1H), 7.08 (dd, 1H), 6.97 (dl, 1H), 6.96 (sl, 1H), 4.41/4.27(2*d, 2H), 3.84 (s, 3H), 3.37/3.09 (m, 2H), 3.16/2.83 (m, 2H), 2.95 (m,2H), 2.09/1.66 (m, 2H), 1.86/1.35 (m, 2H), 1.66 (m, 2H), 1.13/1.06 (m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=465.1941 (465.1949)

Elemental analysis: C=59.94 (59.48); H=6.44 (6.51); N=6.11 (6.03)

RP: −19.240 (589 nm, T=20° C., C=0.6)

Intermediate 138: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[3-(4-chlorophenyl)pyridin-2-yl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 138 is obtained starting from intermediates 129 and 291 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.55 (d, 1H), 7.68 (d, 1H), 7.55 (m,4H), 7.42 (dd, 1H), 3.94 (m, 2H), 3.63/3.44 (2*d, 2H), 3.19 (m, 2H),2.98/2.51 (2*m, 2H), 2.64/2.36 (2*m, 2H), 1.91/1.75 (2*m, 2H), 1.75/1.62(2*m, 2H), 1.4 (s, 18H), 1.33 (s, 9H), 1.23 (m, 2H), 1.18 (t, 3H),0.59/0.34 (m, 2H)

Example 186:(3S)-3-(4-Aminobutyl-1-[[3-(4-chlorophenyl)pyridin-2-yl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 186 is, obtained starting from intermediate 138 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.6 (d, 1H), 7.8 (d, 1H), 7.5 (m, 3H), 7.3(d, 2H), 4.4 (m, 2H), 3.5-3.3 (m, 2H), 3.2 (m, 2H), 2.95 (m, 2H), 2.2(m, 1H), 1.9 (m, 1H), 1.65 (m, 1H), 1.6 (m, 2H), 1.45 (m, 1H), 1.3-1.1(m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=452.1502 (452.1500)

Elemental analysis: C=55.89 (55.82); H=5.56 (6.02); N=9.17 (9.30)

RP: −5.260 (589 nm, T=20° C., C=1.0)

Intermediate 139: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(4-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 139 is obtained starting from intermediates 129 and 221 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1H), 7.31 (d, 2H), 7.17 (m,1H), 7.01 (m, 1H), 7.01 (d, 2H), 3.93 (m, 2H), 3.8 (s, 3H), 3.5/3.32(2*d, 2H), 3.32 (m, 2H), 2.75/2.21 (2*m, 2H), 2.72/2.33 (2*m, 2H),2-1.78 (unresolved peak, 2H), 2-1.78 (unresolved peak, 2H), 1.4/1.33(2*s, 27H), 1.38 (m, 2H), 1.18 (t, 3H), 0.7 (m, 2H)

Example 187:(3S)-3-(4-Aminobutyl)-[[4-fluoro-2-(4-methoxyphenyl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 187 is obtained starting from intermediate 139 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.57 (dd, 1H), 7.3 (d, 2H), 7.19 (td, 1H),7.12 (dd, 1H), 7.08 (d, 2H), 4.32 (AB, 2H), 3.84 (s, 3H), 3.33/3.07 (2m,2H), 3.13/2.8 (2m, 2H), 2.92 (m, 2H), 2.05/1.62 (2m, 2H), 1.83/1.32 (2m,2H), 1.57 (m, 2H), 1.05 (m, 2H)

ESI/FIA/HR and MS/MS [M+H]+=465.1960 (465.1954)

Elemental analysis: C=59.41 (59.48); H=6.76 (6.51); N=6.09 (6.03)

RP: −13.770 (589 nm, T=20° C., C=0.9)

Intermediate 140: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(4-methylphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 140 is obtained starting from intermediates 129 and 288 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1H), 7.33 (2*m, 2H), 7.23(2*d, 4H), 7.18 (dd, 1H), 3.92 (m, 2H), 3.54/3.35 (2*d, 2H), 3.3 (m,2H), 2.74/2.2 (2*m, 2H), 2.74/2.32 (2*m, 2H), 2.36 (s, 3H), 1.95-1.75(m, 2H), 1.95-1.75 (m, 2H), 1.41/1.33 (2*s, 27H), 1.38 (m, 2H), 1.17 (t,3H), 0.71 (m, 2H)

Example 188:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[2-(4-methylphenyl)phenyl]-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 188 is obtained starting from intermediate 140 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6-7.35 (m, 4H), 7.33/7.22 (2d, 4H), 4.33(AB, 2H), 3.33/3.07 (2m, 2H), 3.19/2.8 (2m, 2H), 2:91 (m, 2H), 2.35 (s,3H), 2.06/1.58 (2m, 2H), 1.82/1.32 (2m, 2H), 1.57 (m, 2H), 1.07 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=431.2097 (431.2099)

Elemental analysis: C=64.03 (64.17); H=6.92 (7.26); N=6.45 (6.51)

RP: −13.150 (589 nm, T=20° C., C=0.9)

Intermediate 141: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 141 is obtained starting from intermediates 129 and 271 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.49 (dd, 1H), 7.42 (dd, 2H), 7.29 (t,2H), 7.21 (td, 1H), 7.06 (dd, 1H), 3.92 (m, 2H), 3.49/3.32 (2*d, 2H),3.32 (m, 2H), 2.71/2.2 (2*m, 2H), 2.7/2.34 (2*m, 2H), 1.9-1.65 (m, 2H),1.9-1.65 (m, 2H), 1.4/1.33 (2*s, 27H), 1.38 (m, 2H), 1.18 (t, 3H), 0.67(m, 2H)

Example 189:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 189 is obtained starting from intermediate 141 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.59 (dd, 1H), 7.35 (m, 2H), 7.23 (td, 1H),7.23 (t, 2H), 7.14 (dd, 1H), 4.31 (AB, 2H), 3.36/3.07 (2m, 2H),3.16/2.83 (2m, 2H), 2.92 (m, 2H), 2.06/1.58 (2m, 2H), 1.84/1.33 (2m,2H), 1.58 (m, 2H), 1:07 (m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −111.4/−114.1

ESI/FIA/HR and MS/MS: [M+H]+=453.1750 (453.1754)

Elemental analysis: C=58.26 (58.40); H=5.79 (6.01); N=6.18 (6.19)

RP: −17.770 (589 nm, T=20° C., C=1.2)

Intermediate 142: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-fluoro-2-pyridin-3-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 142 is obtained starting from intermediates 129 and 261 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.6 (dd, 1H), 8.58 (dl, 1H), 7.84 (dt,1H), 7.51 (m, 2H), 7.26 (td, 1H), 7.15 (dd, 1H), 3.93 (m, 2H), 3.42 (AB,2H), 3.33 (m, 2H), 2.67/2.2 (2m, 2H), 2.67/2.35 (2m, 2H), 1.96-1.62 (m,4H), 1.41 (s, 18H), 1.36 (m, 2H), 1.34 (s, 9H), 1.17 (t, 3H), 0.65 (m,2H)

Example 190:(3S)-3-(4-Aminobutyl)-1-[(4-fluoro-2-pyridin-3-ylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 190 is obtained starting from intermediate 142 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 8.62 (dd, 1H), 8.54 (d, 1H), 7.89 (dt, 1H),7.7 (dd, 1H), 7.6 (dd, 1H), 7.34 (td, 1H), 7.23 (dd, 1H), 4.35 (AB, 2H),3.46/3.12 (2m, 2H), 3.18/2.87 (2m, 2H), 2.97 (m, 2H), 2.12/1.67 (2m,2H), 1.88/1.37 (2m, 2H), 1.61 (m, 2H), 1.11 (m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −111

ESI/FIA/HR and MS/MS: [M+H]+=436.1794 (436.1801)

Elemental analysis: C=57.69 (57.93); H=5.69 (6.25); N=9.60 (9.65)

RP: −19.680 (589 nm, T=20° C., C=0.7)

Intermediate 143: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-methoxy-2-phenylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 143 is obtained starting from intermediates 129 and 285 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.47-7.32 (m, 5H), 7.35 (d, 1H), 6.95(dd, 1H), 6.75 (d, 1H), 3.92 (quad., 2H), 3.77 (s, 3H), 3.47/3.27 (dd,2H), 3.32 (t, 2H), 2.75/2.28 (dd, 2H), 2.67/2.16 (dd, 2H), 1.85/1.72(dd, 2H), 1.79 (t, 2H), 1.41 (s, 18H), 1.36 (m, 2H), 1.34 (s, 9H), 1.16(t, 3H), 0.68 (m, 2H)

Example 191:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxy-2-phenylphenyl)-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 191 is obtained starting from intermediate 143 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.54-7.44 (m, 3H), 7.54-7.44 (m, 1H), 7.34.(d, 2H), 6.97 (dd, 1H), 6.86 (df, 1H), 4.34/4.19 (2*d, 2H), 3.33/3.05(2*m, 2H), 3.19/2.78 (2*m, 2H), 2.95 (m, 2H), 2.07/1.63 (2*m, 2H),1.85/1.35 (2*m, 2H), 1.59 (m, 2H), 1.2-1 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=433.1887 (433.1887)

Elemental analysis: C=60.81 (61.10); H=6.31 (6.76); N=6.49 (6.48)

RP: −39.130 (589 nm, T=20° C., C=0.9)

Intermediate 144: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-ethoxy-1-[(4-fluoro-2-pyridin-4-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 144 is obtained starting from intermediates 129 and 262 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.65 (m, 2H), 7.53 (dd, 1H), 7.44 (m,2H), 7.28 (td, 1H), 7.14 (dd, 1H), 3.93 (m, 2H), 3.44 (AB, 2H), 3.32 (m,2H), 2.69/2.21 (2m, 2H), 2.69/2.35 (2m, 2H), 1.96-1.62 (m, 4H), 1.41 (s,18H), 1.36 (m, 2H), 1.33 (s, 9H), 1.17 (t, 3H), 0.66/0.58 (2m, 2H)

Example 192:(3S)-3-(4-Aminobutyl)-1-[(4-fluoro-2-pyridin-4-ylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 192 is obtained starting from intermediate 144 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.63 (d, 2H), 7.67 (dd, 1H), 7.45 (d, 2H),7.33 (td, 1H), 7.21 (dd, 1H), 4.4/4.29 (2*d, 2H), 3.44/3.08 (m, 2H),3.16/2.88 (m, 2H), 2.95 (m, 2H), 2.1/1.65 (m, 2H), 1.86/1.36 (m, 2H),1.6 (m, 2H), 1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=436.1804 (436.1801)

Elemental analysis: C=58.11 (57.93); H=5.71 (6.25); N=9.79 (9.65)

RP: −16.250 (589 nm, T=20° C., C=1.0)

Intermediate 146: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(3-chlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 146 is obtained starting from intermediates 129 and 213 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (sl, 1H), 7.45 (m, 2H),7.45/7.38/7.25 (3m, 4H), 7.33 (dt, 1H), 3.94 (m, 2H), 3.53/3.32 (AB,2H), 3.25 (m, 2H), 2.76/2.37 (2m, 2H), 2.7/2.25 (2m, 2H), 1.95/1.78 (2m,2H), 1.82/1.75 (2m, 2H), 1.41 (s, 18H), 1.33 (s, 9H), 1.33 (m, 2H), 1.18(t, 3H), 0.66/0.57 (2m, 2H)

Example 194:(3S)-3-(4-Aminobutyl)-1-[[2-(3-chlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 194 is obtained starting from intermediate 146 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.63-7.23 (m, 8H), 4.33 (AB, 2H), 3.42/3.1(2m, 2H), 3.17/2.82 (2m, 2H), 2.93 (m, 2H), 2.1/1.63 (2m, 2H), 1.84/1.34(2m, 2H), 1.57 (m, 2H), 1.07 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.1539 (451.1548)

Elemental analysis: C=58.76 (58.60); H=6.46 (6.26); N=6.38 (6.21)

RP: −15.780 (589 nm, T=20° C., C=1.2)

Intermediate 147: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl)-}-1-[[4-chloro-2-(4-chlorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 147 is obtained starting from intermediates 129 and 292 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (d, 2H), 7.5 (d, 1H), 7.45 (dd,1H), 7.41 (d, 2H), 7.27 (d, 1H), 3.94 (m, 2H), 3.5/3.33 (dd, 2H), 3.3(m, 2H), 2.8-2.6 (2m, 2H), 2.35 (dd, 1H), 2.2 (m, 1H), 2-1.7 (m, 4H),1.41 (s, 18H), 1.4-1.3 (m, 2H), 1.33 (s, 9H), 1.18 (t, 3H), 0.68 (m, 2H)

Example 195:(3S)-3-(4-Aminobutyl)-1-[[4-chloro-2-(4-chlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 195 is obtained starting from intermediate 147 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.55-7.5 (2d, 2H), 7.5 (d, 2H), 7.4 (d,1H), 7.28 (d, 2H), 4.3 (dd, 2H), 3.35/3.05 (2m, 2H), 3.15/2.8 (2m, 2H),2.9 (m, 2H), 2.05/1.65 (2m, 2H), 1.8/1.3 (2m, 2H), 1.55 (m, 2H), 1.05(m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=485.1162 (485.1163)

Elemental analysis: C=55.11 (54.44); H=5.26 (5.61); N=5.87 (5.77)

RP: −17.410 (589 nm, T=19° C., C=1.0)

Intermediate 148: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[2-(6-methoxypyridin-3-yl)benzyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 148 is obtained starting from intermediates 129 and 237 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.1 (d, 1H), 7.75 (dd, 1H), 7.5-7.2 (m,4H), 6.9 (d, 1H), 3.9 (s, 3H), 3.9 (m, 2H), 3.55/3.35 (dd, 2H), 3.3 (m,2H), 2.75/2.2 (2m, 2H), 2.7/2.35 (2dd, 2H), 1.9/1.8 (2m, 2H), 1.8 (m,2H), 1.4 (s, 18H), 1.35 (m, 2H), 1.35 (s, 9H), 1.2 (t, 3H), 0.65 (m, 2H)

Example 196:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[2-(6-methoxypyridin-3-yl)benzyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 196 is obtained starting from intermediate 148 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.05 (d, 1H), 7.75 (dd, 1H), 7.6 (m, 1H),7.5 (m, 2H), 7.4 (m, 1H), 7 (d, 1H), 4.3 (dd, 2H), 3.9 (s, 3H),3.45/3.15 (2m, 2H), 3.2/2.85 (2dd, 2H), 2.9 (m, 2H), 2.1/1.7 (2m, 2H),1.8/1.35 (2m, 2H), 1.6 (m, 2H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=448.2009 (448.2001)

Elemental analysis: C=58.81 (59.05); H=6.79 (6.76); N=9.31 (9.39)

RP: −11.510 (589 nm, T=19° C., C=0.9)

Intermediate 149: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(4-fluorophenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 149 is obtained starting from intermediate 129 and2-(4-fluorophenyl)benzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.47 (dd, 1H), 7.39/7.33 (2*m, 2H),7.39 (dd, 2H), 7.27 (t, 2H), 7.21 (dd, 1H), 3.93 (m, 2H), 3.52/3.34(2*d, 2H), 3.38-3.22 (m, 2H), 2.75/2.21 (2*m, 2H), 2.7/2.35 (2*m, 2H),1.98-1.72 (m, 2H), 1.98-1.72 (m, 2H), 1.41/1.34 (2*s, 27H), 137 (m, 2H),1.19 (t, 3H), 0.68 (m, 2H)

Example 197:(3S)-3-(4-Aminobutyl)-1-[[2-(4-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 197 is obtained starting from intermediate 149 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (d, 1H), 7.52 (m, 2H), 7.4 (d, 1H),7.35 (dd, 2H), 7.24 (dd, 2H), 4.41/4.29 (dd, 2H), 3.39/3.1 (2*m, 2H),3.19/2.88 (2*m, 2H), 2.93 (m, 2H), 2.09/1.65 (2*m, 2H), 1.85/1.59 (2*m,2H), 1.59/1.35 (2*m, 2H), 1.2-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=435.1843 (435.1843)

Elemental analysis: C=60.70 (60.82); H=6.56 (6.50); N=6.49 (6.45)

RP: −23.350 (589 nm, T=20° C., C=0.7)

Intermediate 150: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(4-chlorophenyl)-4-fluorophenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 150 is obtained starting from intermediates 129 and 220 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (d, 2H), 7.5 (m, 1H), 7.42 (d,2H), 7.22 (dt, 1H), 7.07 (dd, 1H), 4-3.86 (m, 2H), 3.5/3.32 (2*d, 2H),3.4-3.25 (m, 2H), 2.71/2.21 (2*m, 2H), 2.71/2.35 (2*m, 2H), 1.99-1.72(m, 2H), 1.99-1.72 (m, 2H), 1.41/1.33 (2*s, 27H), 1.38 (m, 2H), 1.19 (t,3H), 0.68 (m, 2H)

Example 198:(3S)-3-(4-Aminobutyl)-[[2-(4-chlorophenyl)-4-fluorophenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 198 is obtained starting from intermediate 150 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.62 (dd, 1H), 7.54 (d, 2H), 7.35 (d, 2H),7.25 (td, 1H), 7.17 (dd, 1H), 4.39/4.28 (2*d, 2H), 3.4/3.09 (2*m, 2H),3.13/2.84 (2*m, 2H), 2.95 (m, 2H), 2.09/1.65 (2*m, 2H), 1.86/1.36 (2*m,2H), 1.6 (m, 2H), 1.09 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=469.1452 (469.1454)

Elemental analysis: C=56.19 (56.35); H=5.57 (5.80); N=5.97 (5.97)

RP: −12.560 (589 nm, T=20° C., C=0.7)

Intermediate 151: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(2-naphthalen-1-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 151 is obtained starting from intermediates 129 and 228 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8 (m, 2H), 7.65-7.2 (m, 9H), 3.85 (m,2H), 3.4 (m, 2H), 3.35-3 (2dd, 2H), 2.65/2.2 (2m, 2H), 2.5/2 (2m, 2H),1.9-1.5 (m, 4H), 1.4 (2s, 18H), 1.35 (m, 2H), 1.3 (2s, 9H), 1.1 (t, 3H),0.65 (m, 2H)

Example 199:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[2-naphthalen-1-ylphenyl)-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 199 is obtained starting from intermediate 151 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8 (m, 2H), 7.75-7.3 (m, 9H), 4.35-3.8 (2dd,2H), 3.4/2.95 (2m, 2H), 3.2/2.7 (2m, 2H), 2.9 (m, 2H), 2.05/1.55 (2m,2H), 1.75/1.25 (2m, 2H), 1.5 (m, 2H), 1.2-0.7 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=467.2109 (467.2099)

Elemental analysis: C=66.50 (66.94); H=6.26 (6.70); N=6.08 (6.00)

RP: −25.420 (589 nm, T=19° C., C=1.0)

Intermediate 152: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarboxy)amino]butyl}-1-[(2-tert-butylphenyl)methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 152 is obtained starting from intermediate 129 and2-tert-butylbenzaldehyde in accordance with procedure F describedhereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.6-7.15 (3m, 4H), 4 (m, 2H), 3.75 (dd,2H), 3.45-3.3 (m, 2H), 3-2.75 (2m, 2H), 2.5 (dd, 2H), 2.4 (m, 2H),2-1.85 (m, 2H), 1.4 (m, 2H), 1.4 (s, 18H), 1.4 (t, 9H), 1.35 (s, 9H),1.2 (t, 3H), 0.95-0.7 (m, 2H)

Example 200:(3S)-3-(4-Aminobutyl)-1-[(2-tert-butylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 200 is obtained starting from intermediate 152 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.57/7.46 (2m, 2H), 7.36 (m, 2H), 4.65 (AB,2H), 3.68/3.41 (2m, 2H), 3.46/3.22 (2m, 2H), 2.89 (m, 2H), 2.25/1.75(2m, 2H), 1.9/1.46 (2m, 2H), 1.56 (quint, 2H), 1.35 (s, 9H), 1.13 (m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=397.2253 (397.2256)

Elemental analysis: C=61.19 (60.59); H=8.40 (8.39); N=7.29 (7.07)

RP: −41.120 (589 nm, T=19° C., C=0.9)

Intermediate 153: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(4-fluoro-3-methoxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 153 is obtained starting from intermediates 129 and 273 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.51 (dd, 1H), 7.28 (dd, 1H), 7.21 (dt,1H), 7.09 (m, 1H), 7.09 (m, 1H), 6.93 (m, 1H), 3.93 (m, 2H), 3.88 (s,3H), 3.52/3.35 (2*d, 2H), 3.4-3.25 (m, 2H), 2.72/2.21 (2*m, 2H),2.72/2.34 (2*m, 2H), 1.9-1.65 (m, 2H), 1.9-1.65 (m, 2H), 1.41/1.33 (2*s,27H), 1.38 (m, 2H), 1.18 (t, 3H), 0.7 (m, 2H)

Example 201:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(4-fluoro-3-methoxyphenyl)-phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 201 is obtained starting from intermediate 153 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.6 (dd, 1H), 7.25 (m, 2H), 7.15 (m,2H), 6.95 (m, 1H), 4.4/4.3 (2*d, 2H), 3.9 (s, 3H), 3.5-3.3 (m, 1H),3.2-3.05 (m, 2H), 2.95 (m, 2H), 2.9 (dd, 1H), 2.05 (m, 1H), 1.85 (m,1H), 1.65 (m, 1H), 1.6 (m, 2H), 1.35 (m, 1H), 1.2-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=483.1854 (483.1855)

Elemental analysis: C=57.37 (5726); H=5.95 (6.06); N=5.86 (5.81)

RP: −21.910 (589 nm, T=21° C., C=1.1)

Intermediate 154: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(2-isoquinolin-4-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 154 is obtained starting from intermediates 129 and 264 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.35 (d, 1H), 8.32 (d, 1H), 8.21 (m,1H), 7.71 (m, 2H), 7.6 (2*d, 1H), 7.5 (2*t, 1H), 7.42 (t, 1H), 7.31 (m,1H), 7.25 (m, 1H), 3.87 (m, 2H), 3.45-3.3 (m, 2H), 3.32/3.2/3.05 (m,2H), 2.62/2.2 (m, 2H), 2.58/2 (m, 2H), 1.8-1.25 (m, 6H), 1.6 (m, 2H),1.42/1.4 (2*s, 18H), 1.32/1.3 (2*s, 9H), 1.1 (m, 3H)

³¹P NMR: (400 MHz, dmso-d6) δ ppm 44.94

Example 202:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[(2-isoquinolin-4-ylphenyl)-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 202 is obtained starting from intermediate 154 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 9.3 (s, 1H), 8.35/8 (2*s, 1H), 8.2 (m, 1H),7.8-7.4 (m, 7H), 4.4-3.8 (2AB, 2H), 3.6-3.2/3 (m, 2H), 3.1/2.7 (m, 2H),2.91 (m, 2H), 2.1/1.55 (m, 2H), 1.75/1.25 (m, 2H), 1.6 (m, 2H),1.15-0.75 (m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 25.29

ESI/FIA/HR and MS/MS: [M+H]+=468.2046 (468.2047)

Elemental analysis: C=64.83 (64.23); H=5.86 (6.47); N=9.17 (8.99)

Intermediate 155: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(2-methoxypyridin-4-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 155 is obtained starting from intermediates 129 and 244 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.2 (d, 1H), 7.5 (m, 1H), 7.45-7.3 (2m,2H), 7.25 (m, 1H), 7 (dd, 1H), 6.8 (sl, 1H), 3.9 (m, 2H), 3.9 (s, 3H),3.6/3.35 (dd, 2H), 3.3 (m, 2H), 2.75/2.35 (dd, 2H), 2.7/2.25 (2m, 2H),1.95/1.75 (2m, 2H), 1.75 (m, 2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.3 (m,2H), 1.2 (t, 3H), 0.7-0.5 (m, 2H)

Example 203:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[2-(2-methoxypyridin-4-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 203 is obtained starting from intermediate 155 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.18 (d, 1H), 7.65-7.35 (m, 4H), 7.02 (d,1H), 6.85 (s, 1H), 4.35 (dd, 2H), 3.9 (s, 3H), 3.65-3 (m, 3H), 3-2.8 (m,3H), 2.1/1.7 (2m, 2H), 1.85/1.35 (2m, 2H), 1.6 (m, 2H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=448.1989 (448.2001)

Elemental analysis: C=59.15 (59.05); H=6.25 (6.76); N=9.64 (939)

RP: −11.440 (589 nm, T=19.5° C., C=0.9)

Example 204:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-(2-oxo-1H-pyridin-4-yl)phenyl]methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 204 is obtained starting from intermediate 155 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.65-7.3 (m, 4H), 7.6 (d, 1H), 6.55 (s,1H), 6.5 (d, 1H), 4.35 (dd, 2H), 3.5 (2m, 2H), 3.25/2.9 (2m, 2H), 2.9(m, 2H), 2.15/1.7 (2m, 2H), 1.85/1.4 (2m, 2H), 1.6 (m, 2H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=434.1838 (434.1839)

Elemental analysis: C=58.88 (58.19); H=6.31 (6.51); N=9.95 (9.69)

RP: −10.530 (589 nm, T=19° C., C=1.0)

Intermediate 156: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-{2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]benzyl}-1,4-azaphosphinane-3-carboxylate

Intermediate 156 is obtained starting from intermediates 129 and 293 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.6 (d, 1H), 7.6-7.2 (m, 4H), 6.3 (d,1H), 4.9-4.8 (dd, 1H), 4-3.8 (m, 4H), 3.5-3.2 (m, 4H), 2.85-2:6 (m, 2H),2.5-2.1 (m, 3H), 2-1.65 (m, 6H), 1.5-1.25 (m, 5H), 1.4 (s, 18H), 1.35(s, 9H), 1.2 (t, 3H), 0.85-0.6 (m, 2H)

Example 205:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[2-(1H-pyrazol-3-yl)benzyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 205 is obtained starting from intermediate 156 in accordancewith procedure D described hereinbefore.

¹H NMR: (300/400/500 MHz, dmso-d6) δ ppm 7.62 (d, 1H), 7.6 (d, 1H), 7.38(t, 1H), 7.33 (d, 1H), 7.26 (t, 1H), 6.55 (d, 1H), 4.32/4.05 (dd, 2H),3.59/3.19 (dd, 2H), 3.33/2.93 (dd, 2H), 2.74 (m, 2H), 2.11/1.61 (2*m,2H), 1.73/1.29 (2*m, 2H), 1.41 (m, 2H), 1.04/0.88 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=407.1843 (407.1848)

Elemental analysis: C=56.28 (56.15); H=6.42 (6.70); N=13.82 (13.79)

RP: −84.390 (589 nm, T=19° C., C=1.1)

Intermediate 157: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(2-chlorophenyl)-4-fluorophenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 157 is obtained starting from intermediates 129 and 253 inaccordance with procedure F described hereinbefore.

¹H NMR: (300/400 MHz, dmso-d6) δ ppm 7.65-7.4 (m, 4H), 7.25 (m, 2H), 7(m, 1H), 3.9 (m, 2H), 3.35 (d, 1H), 3.3 (m, 2H), 3.15 (d, 1H), 2.8-2.55(m, 2H), 2.3 (m, 1H), 2.1 (m, 1H), 1.95-1.7 (m, 4H), 1.45 (m, 2H),1.45/1.35 (2*s, 27H), 1.15 (t, 3H), 0.75 (m, 2H)

¹⁹F NMR: (300/400 MHz, dmso-d6) δ ppm −114.5

ESI/FIA/HR and MS/MS: [M+H]+=753.3436 (753.3441)

Example 206:(3S)-3-(4-Aminobutyl)-1-[[2-(2-chlorophenyl)-4-fluorophenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 206 is obtained starting from intermediate 157 in accordancewith procedure D described hereinbefore.

¹H NMR: (300/400 MHz, dmso-d6) δ ppm 7.7-7.35 (m, 4H), 7.35-7.2 (m, 2H),7.1 (m, 1H), 4.1 (sl, 2H), 3.7-3 (m, 3H), 3-2.7 (m, 3H), 2.2-2 (m, 1H),1.8 (m, 1H), 1.65 (m, 1H), 1.55 (m, 2H), 1.45-1 (m, 3H)

ESI/FIA/HR and MS/MS: [M+H]+=469.1456 (469.1454)

Elemental analysis: C=56.86 (56.35); H=5.21 (5.80); N=5.91 (5.97)

RP: −15.060 (589 nm, T=20° C., C=1.0)

Intermediate 158: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(2,3-dimethoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 158 is obtained starting from intermediate 129 and2-(2,3-dimethoxyphenylbezaldehyde) in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.5 (m, 1H), 7.35-7.2 (2m, 2H), 7.1 (m,1H), 7.05-7 (2m, 2H), 6.7 (dd; 1H), 3.9 (m, 2H), 3.85 (s, 3H), 3.45 (s,3H), 3.4 (m, 2H), 3.35 (dd, 2H), 2.7/2.4 (2m, 2H), 2.65/2.2 (2m, 2H),1.95-1.7 (m, 4H), 1.45 (s, 18H), 1.4 (m, 2H), 1.35 (s, 9H), 1.2 (t, 3H),0.9 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=761.4136 (761.4142)

Example 207:(3S)-3-(4-Aminobutyl)-1-[[2-(2,3-dimethoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 207 is obtained starting from intermediate 158 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.65-7.35 (m, 4H), 7.25 (m, 1H), 7.2 (m,1H), 6.9-6.8 (2dd, 1H), 4.35-3.9 (2dd, 2H), 3.86 (s, 3H), 3.7-2.65 (m,4H), 3.4-3.35 (2s, 3H), 2.9 (m, 2H), 2.5-1.6 (m, 4H), 1.6 (m, 2H),1.5-0.9 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=477.2149 (477.2154)

Elemental analysis: C=61.06 (60.50); H=6.99 (6.98); N=5.97 (5.88)

Intermediate 159: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-hydroxy-1-[[2-(2-methylsulphonylphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 159 is obtained starting from intermediate 129 and2-(2-methylsulphonylphenyl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (300/400 MHz, dmso-d6) δ ppm 8.1 (d, 1H), 7.8-7.65 (2*m, 2H),7.55 (d, 1H), 7.45 (m, 1H), 7.3 (d, 1H), 7.25 (d, 1H), 7.25 (m, 1H),3.95 (m, 2H), 3.5-3.25 (m, 4H), 3.1 (dd, 1H), 2.9-2.6 (2*m, 2H), 2.85(2*s, 3H), 2.45 (m, 1H), 2.3 (m, 1H), 2.1 (m, 1H), 2-1.65 (m, 4H),1.5-1.3 (4s, 27H), 1.2 (m, 3H), 0.75 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=779.3696 (779.3701)

Example 208:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[2-(2-methylsulphonylphenyl)-phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 208 is obtained starting from intermediate 159 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.2 (d, 1H), 7.9/7.8 (2*m, 2H), 7.8-7.4(m, 4H), 7.55 (d, 1H), 4.4-3.8 (4d, 2H), 3.8-3.5 (m, 1H), 3.5-2.85 (m,5H), 3.1/3 (2*s, 3H), 2.4-1.85 (m, 2H), 1.8 (m, 1H), 1.7 (m, 2H),1.6-1.1 (m, 3H)

ESI/FIA/HR and MS/MS: [M+H]+=495.1716 (495.1713)

Elemental analysis: C=55.39 (55.86); H=5.77 (6.32); N=5.61 (5.66);S=6.24 (6.48)

Intermediate 160: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(2-naphthalen-2-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 160 is obtained starting from intermediates 129 and 240 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8-7.3 (m, 11H), 3.9 (m, 2H), 3.6/3.4(dd, 2H), 3.3 (m, 2H), 2.75/2.3 (2dd, 2H), 2.7/2.2 (2m, 2H), 1.9/1.7(2m, 2H), 1.75 (m, 2H), 1.4 (s, 18H), 1.3 (m, 2H), 1.3 (s, 9H), 1.15 (t,3H), 0.65 (m, 2H)

Example 209:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[(2-naphthalen-2-ylphenyl)-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 209 is obtained starting from intermediate 160 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 8-7.4 (m, 11H), 4.35 (dd, 2H), 3.35/3 (2m,2H), 3.1/2.7 (2dd, 2H), 2.8 (m, 2H), 2/1.6 (2m, 2H), 1.75/1.2 (2m, 2H),1.5 (m, 2H), 0.9 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=467.2095 (467.2099)

Elemental analysis: C=67.07 (66.94); H=6.46 (6.70); N=5.88 (6.00)

RP: −8.570 (589 nm, T=19° C., C=0.8)

Intermediate 161: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[4-chloro-2-(4-fluorophenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 161 is obtained starting from intermediate 129 and4-chloro-2-(4-fluorophenyl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.5 (d, 1H), 7.45 (dd, 1H), 7.4 (dd,2H), 7.29 (t, 2H), 7.25 (d, 1H), 3.92 (m, 2H), 3.5/3.3 (AB, 2H), 3.3 (m,2H), 2.72/2.2 (2*m, 2H), 2.67/2.35 (2*m, 2H), 2-1.7 (m, 2H), 1.8 (m,2H), 1.4 (s, 18H), 1.35 (m, 2H), 1.32 (s, 9H), 1.18 (t, 3H), 0.7 (m, 2H)

³¹P NMR: (400 MHz, dmso-d6) δ ppm 44.88, −113.8

Example 210:(3S)-3-(4-Aminobutyl)-1-[[4-chloro-2-(4-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 210 is obtained starting from intermediate 161 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.57 (d, 1H), 7.51 (dd, 1H), 7.45 (d, 1H),7.36 (m, 2H), 7.24 (t, 2H), 4.4/4.27 (AB, 2H), 3.38/3.1 (m, 2H),3.2/2.85 (m, 2H), 2.94 (m, 2H), 2.09/1.65 (m, 2H), 1.85/1.35 (m, 2H),1.59 (m, 2H), 1.1 (m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 25.4, −110.5

ESI/FIA/HR and MS/MS: [M+H]+=469.1455 (469.1454)

Elemental analysis: C=56.27 (56.35); H=5.43 (5.80); N=5.97 (5.97);Cl=7.28 (7.56)

RP: −28.440 (589 nm, T=20° C., C=0.9)

Intermediate 162: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(4-hydroxyphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 162 is obtained starting from intermediates 129 and 265 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.6 (sl, 1H), 7.49 (dd, 1H), 7.18 (d,2H), 7.12 (td, 1H), 6.98 (dd, 1H), 6.81 (d, 2H), 3.92 (m, 2H), 3.5/3.3(AB, 2H), 3.3 (m, 2H), 2.72/2.2 (2*m, 2H), 2.67/2.35 (2*m, 2H), 2-1.7(m, 2H), 1.8 (m, 2H), 1.4 (s, 18H), 1.35 (m, 2H), 1.32 (s, 9H), 1.18 (t,3H), 0.7 (m, 2H)

³¹P NMR: (400 MHz, dmso-d6) δ ppm 45.1, −114.8

Example 211:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(4-hydroxyphenyl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 211 is obtained starting from intermediate 162 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.47 (dd, 1H), 7.12 (d, 2H), 7.09 (td, 1H),7.01 (dd, 1H), 6.88 (d, 2H), 4.3/4.16 (AB, 2H), 3.23/2.98 (m, 2H), 3/2.7(m, 2H), 2.81 (m, 2H), 1.96/1.55 (m, 2H), 1.72/1.21 (m, 2H), 1.49 (m,2H), 0.95 (m, 2H)

³¹P NMR: (400 MHz, D2O) δ ppm 25.4, −113

ESI/FIA/HR and MS/MS: [M+H]+=451.1794 (451.1793)

Elemental analysis: C=58.16 (58.66); H=5.71 (6.27); N=6.30 (6.22)

RP: −16.520 (589 nm, T=20° C., C=0.9)

Intermediate 163: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 163 is obtained starting from intermediates 129 and 250 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 8 (s, 1H), 7.7 (s, 1H), 7.4 (dd, 1H),7.2 (dd, 1H), 7.05 (td, 1H), 3.97 (m, 2H), 3.9 (s, 3H), 3.6/3.4 (dd,2H), 3.25 (m, 2H), 3/2.35 (2m, 2H), 2.8/2.45 (2m, 2H), 2 (m, 2H), 1.8(m, 2H), 1.4 (s, 18H), 1.35 (s, 9H), 1.3 (m, 2H), 1.2 (t, 3H), 0.65 (m,2H)

Example 212:(3S)-3-(4-Aminobutyl)-1-[4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 212 is obtained starting from intermediate 163 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.81 (s, 1H), 7.7 (s, 1H), 7.6 (dd, 1H),7.2 (m, 2H), 4.45 (dd, 2H), 3.95 (s, 3H), 3.5/3.25 (2m, 2H), 3.3/3 (2m,2H), 3 (m, 2H), 2.1/1.75 (2m, 2H), 1.9/1.4 (2m, 2H), 1.65 (m, 2H), 1.15(m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −110.5

ESI/FIA/HR and MS/MS: [M+H]+=439.1905 (439.1910)

Elemental analysis: C=54.79 (54.79); H=6.05 (6.44); N=12.61 (12.78)

RP: −18.620 (589 nm, T=19° C., C=0:9)

Intermediate 164: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-fluoro-2-thiophen-2-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 164 is obtained starting from intermediates 129 and 246 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.66 (dd, 1H), 7.47 (dd, 1H), 7.31 (dd,1H), 7.25 (dd, 1H), 7.2 (dd, 1H), 7.16 (td, 1H), 3.97 (m, 2H), 3.63/3.4(dd, 2H), 3.25 (m, 2H), 2.88/2.32 (2m, 2H), 2.79/2.42 (dd, 2H), 2.05-1.9(m, 2H), 1.82 (m, 2H), 1.39 (s, 18H), 1.33 (s, 9H), 1.3 (m, 2H), 1.2 (t,3H), 0.7-0.4 (2m, 2H)

¹⁹F NMR: (300 MHz, dmso-d6) δ ppm −113.9

Example 213:(3S)-3-(4-Aminobutyl)-1-[(4-fluoro-2-thiophen-2-ylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 213 is obtained starting from intermediate 164 in accordancewith procedure D described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.65 (dd, 1H), 7.55 (dd, 1H), 7.29 (dd,1H), 7.2 (td, 1H), 7.15 (m, 2H), 4.5 (dd, 2H), 3.5/3.2 (2m, 2H), 3.3/2.9(2m, 2H), 2.9 (m, 2H), 2.1/1.75 (2m, 2H), 1.85/1.4 (2m, 2H), 1.6 (m,2H), 1.1 (m, 2H)

¹⁹F NMR: (300 MHz, dmso-d6) δ ppm −110

ESI/FIA/HR and MS/MS: [M+H]+=441.1405 (441.1413)

Elemental analysis: C=54.66 (54.54); H=5.90 (5.95); N=6.35 (6.36);S=7.27 (7.28)

RP: −13.110 (589 nm, T=19.5° C., C=0.7)

Intermediate 165: tert-Butyl(3S)-3-{4-bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(2-isoquinolin-5-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 165 is obtained starting from intermediates 129 and 216 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.4 (s, 1H), 8.45 (d, 1H), 8.2 (m, 1H),7.75 (m, 1H), 7.65 (m, 1H), 7.6-7.4 (m, 3H), 7.2 (m, 1H), 7.15 (2*d,1H), 3.95-3.7 (m, 2H), 3.5-3 (m, 4H), 3.5-3.3 (m, 2H), 2.7-2.4 (m, 2H),2.2 (m, 1H), 2 (m, 1H), 1.85 (m, 1H), 1.8 (m, 2H), 1.7-1.5 (m, 1H),1.5-1.25 (4s, 27H), 1.1 (t, 3H), 0.75-0.5 (m, 2H)

Example 214:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[2-isoquinolin-5-ylphenyl)-methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 214 is obtained starting from intermediate 165 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 9.25 (s, 1H), 8.3 (dd, 1H), 8.2 (m, 1H),7.85-7.55 (m, 5H), 7.35 (m, 1H), 7.3 (d, 1H), 4.45-3.8 (4d, 2H),3.65-3.05 (m, 2H), 3.05-2.8 (m, 3H), 2.7 (m, 1H), 2.1 (m, 1H), 1.75 (m,1H), 1.7-1.5 (m, 3H), 1.35-0.6 (m, 3H)

ESI/FIA/HR and MS/MS: [M+H]+=468.2051 (468.2047)

Elemental analysis: C=64.96 (64.23); H=6.08 (6.47); N=9.03 (8.99)

Intermediate 166: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-fluoro-2-naphthalen-2-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 166 is obtained starting from intermediates 129 and 247 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8-7.9 (m, 3H), 7.9 (sl, 1H), 7.6-7.5(m, 4H), 7.25 (td, 1H), 7.15 (dd, 1H), 3.9 (m, 2H), 3.6/3.4 (dd, 2H),3.3 (m, 2H), 2.75/2.3 (2m, 2H), 2.7/2.2 (2m, 2H), 1.9/1.75 (2m, 2H),1.75 (m, 2H), 1.4 (s, 18H), 1.3 (s, 9H), 1.3 (m, 2H), 1.15 (t, 3H), 0.7(m, 2H)

Example 215:(3S)-3-(4-Aminobutyl)-1-[(4-fluoro-2-naphthalen-2-ylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 215 is obtained starting from intermediate 166 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.08 (d, 1H), 8 (m, 2H), 7.95 (d, 1H), 7.7(dd, 1H), 7.65 (m, 2H), 7.54 (dd, 1H), 7.3 (m, 1H), 7.3 (dd, 1H),4.65-4.2 (m, 2H), 3.35/3.05 (2m, 2H), 3.05/2.8 (2m, 2H), 2.85 (m, 2H),2/1.65 (2m, 2H), 1.85/1.35 (2m, 2H), 1.55 (m, 2H), 0.9 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=485.2002 (485.2005)

Elemental analysis: C=63.97 (64.45); H=6.21 (6.24); N=5.93 (5.78)

RP: −6.790 (589 nm, T=19° C., C=0.7)

Intermediate 167: tert-Butyl(3S)-3-{4-[bis(tert-butyloxycarbonyl)amino]butyl}-1-[[2-(1-benzothiophen-2-yl)-4-fluorophenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 167 is obtained starting from intermediates 129 and 217 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.05 (d, 1H), 7.9 (d, 1H), 7.6 (s, 1H),7.55 (dd, 1H), 7.4 (m, 2H), 7.35 (d, 1H), 7.3 (m, 1H), 3.95 (m, 2H),3.75 (d, 1H), 3.5 (d, 1H), 3.25 (m, 2H), 2.95 (m, 1H), 2.8 (m, 1H), 2.45(dd, 1H), 2.35 (m, 1H), 2.05-1.6 (m, 4H), 1.42 (m, 2H), 1.4 (s, 18H),1.35 (s, 9H), 1.2 (t, 3H), 0.65 (m, 1H), 0.55 (m, 1H)

Example 216:(3S)-3-(4-Aminobutyl)-1-[[2-(1-benzothiophen-2-yl)-4-fluorophenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 216 is obtained starting from intermediate 167 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.95/7.9 (2*d, 2H), 7.65 (m, 1H), 7.45 (m,2H), 7.4 (s, 1H), 7.3 (m, 2H), 4.55/4.4 (2*d, 2H), 3.6-3.4 (m, 1H), 3.25(m, 1H), 3.15 (m, 1H), 2.9 (dd, 1H), 2.85 (m, 2H), 2.1 (m, 1H), 1.85 (m,1H), 1.65 (m, 1H), 1.6-0.85 (m, 5H)

ESI/FIA/HR and MS/MS: [M+H]+=491.1565 (491.1564)

Elemental analysis: C=59.10 (58.77); H=5.38 (5.75); N=5.84 (5.71);S=6.42 (6.54)

RP: 0.930 (589 nm, T=20.5° C., C=1.0)

Intermediate 168: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[4-fluoro-2-(1-methyl-1H-imidazol-5-yl)benzyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 168 is obtained starting from intermediates 129 and 248 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.75 (s, 1H), 7.56 (2d, 1H), 7.29 (2t,1H), 7.15 (2d, 1H), 6.9 (s, 1H), 3.95 (m, 2H), 3.5-3.25 (m, 4H), 3.4 (s,3H), 2.9/2.2 (2m, 2H), 2.65/2.3 (2m, 2H), 1.95/1.85 (2m, 2H), 1.85 (m,2H), 1.4 (m, 2H), 1.4 (2s, 18H), 1.35 (2s, 9H), 1.2 (t, 3H), 1.1-0.65(m, 2H)

Example 217:(3S)-3-(4-Aminobutyl)-1-[4-fluoro-2-(1-methyl-1H-imidazol-5-yl)benzyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 217 is obtained starting from intermediate 168 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.8 (s, 1H), 7.68 (dd, 1H), 7.33 (td, 1H),7.22 (dd, 1H), 7.1 (s, 1H), 4.25/4.18 (AB, 2H), 3.6/3.2 (2m, 2H), 3.45(s, 3H), 3.3/3 (2m, 2H), 2.95 (m, 2H), 2.12/1.71 (2m, 2H), 1.9/1.42 (2m,2H), 1.6 (m, 2H), 1.3-1 (m, 2H)

¹⁹F NMR: (400 MHz, D2O) δ ppm −109.75

ESI/FIA/HR and MS/MS: [M+H]+=439.1905 (439.1905)

Elemental analysis: C=54.41 (54.79); H=6.12 (6.44); N=12.74 (12.78)

RP: −27.720 (589 nm, T=20° C., C=0.7)

Intermediate 169: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[4-chloro-2-(4-methylphenyl)phenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 169 is obtained starting from intermediate 129 and4-chloro-2-(4-methylphenyl)benzaldehyde in accordance with procedure Fdescribed hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.52 (d, 1H), 7.4 (dd, 1H), 7.25 (dd,4H), 7.2 (d, 1H), 3.9 (m, 2H), 3.5/2.8 (dd, 2H), 2.8 (m, 2H), 2.75/2.2(2m, 2H), 2.65/2.3 (2dd, 2H), 2.35 (s, 3H), 1.95/1.8 (2m, 2H), 1.8 (m,2H), 1.4 (s, 18H), 1.35 (m, 2H), 1.35 (s, 9H), 1.18 (t, 3H), 0.7 (m, 2H)

Example 218:(3S)-3-(4-Aminobutyl)-1-{[4-chloro-2-(4-methylphenyl)phenyl]methyl}-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 218 is obtained starting froth intermediate 169 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.58 (d, 1H), 7.5 (dd, 1H), 7.42 (d, 1H),7.38 (d, 2H), 7.23 (d, 2H), 4.4/4.25 (AB, 2H), 3.35/3.1 (2m, 2H),3.2/2.81 (2m, 2H), 2.95 (m, 2H), 2.39 (s, 3H), 2.09/1.68 (2m, 2H),1.85/1.35 (2m, 2H), 1.6 (m, 2H), 1.2-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=465.1707 (465.1704)

Elemental analysis: C=60.11 (59.42); H=6.34 (6.50); N=6.09 (6.03)

RP: −26.100 (589 nm, T=20° C., C=0.3)

Intermediate 170: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[2-(1,2-dimethyl-1H-imidazol-5-yl)-4-fluorobenzyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 170 is obtained starting from intermediates 129 and 274 inaccordance with procedure F described hereinbefore.

¹H NMR: (300/400 MHz, dmso-d6) δ ppm 7.55 (dd, 1H), 7.2 (m, 1H), 7 (d,1H), 6.75 (s, 1H), 4.05-3.7 (m, 4H), 3.5-3.3 (2*d, 2H), 3.25 (s, 3H),3-2.2 (m, 4H), 2.35 (s, 3H), 2-1.3 (m, 6H), 1.4 (3s, 27H), 1.25 (m, 3H),0.85 (m, 2H)

Example 219:(3S)-3-(4-Aminobutyl)-1-[2-(1,2-dimethyl-1H-imidazol-5-yl)-4-fluorobenzyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 219 is obtained starting from intermediate 170 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.75 (dd, 1H), 7.55 (s, 1H), 7.5 (m, 1H),7.3 (dd, 1H), 4.25 (s, 2H), 3.55 (m, 1H), 3.45 (s, 3H), 3.4 (in, 1H),3.25 (m, 1H), 3.15 (dd, 1H), 2.95 (t, 2H), 2.65 (s, 3H), 2.15 (m, 1H),1.9 (m, 1H), 1.75 (m, 1H), 1.65 (m, 2H), 1.45 (m, 1H), 1.3 (m, 1H), 1.15(m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=453.2058 (453.2061)

Elemental analysis: C=46.18 (47.29); H=5.24 (5.86); N=10.02 (10.50)

RP: −28.200 (589 nm, T=20° C., C=1.0)

Intermediate 171: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[4-fluoro-2-imidazo[1,2-a]pyridin-3-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 171 is obtained starting from intermediates 129 and 234 inaccordance with procedure F described hereinbefore.

¹H NMR: (300 MHz, dmso-d6) δ ppm 7.9 (d, 1H), 7.65 (m, 2H), 7.65 (s,1H), 7.35-7.2 (m, 3H), 6.9 (m, 1H), 3.9 (quad., 2H), 3.35 (t, 2H),3.35/3.25 (2*d, 2H), 2.8-2.4 (m, 3H), 2.4 (dd, 1H), 2.2 (m, 1H), 1.9-1.6(m, 3H), 1.5-1.3 (m, 2H), 1.45 (s, 18H), 1.35 (s, 9H), 1.15 (t, 3H),1-0.75 (m, 2H)

Example 220:(3S)-3-(4-Aminobutyl)-1-[(4-fluoro-2-imidazo[1,2-a]pyridin-3-ylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 220 is obtained starting from intermediate 171 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.05 (d, 1H), 7.75 (dd, 1H), 7.7 (d, 1H),7.7 (s, 1H), 7.45 (m, 1H), 7.4 (m, 1H), 7.3 (d, 1H), 7 (m, 1H), 4.6-4(m, 2H), 3.45 (m, 1H), 3.05 (m, 2H), 2.9 (m, 2H), 2.8 (dd, 1H), 2.1 (m,1H), 1.8 (m, 1H), 1.65 (m, 1H), 1.55 (m, 2H), 1.3 (m, 1H), 0.95 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=475.1906 (475.1905)

Elemental analysis: C=58.69 (58.22); H=5.71 (5.95); N=11.94 (11.81)

RP: −27.190 (589 nm, T=20° C., C=1.0)

Intermediate 172: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(2-methoxypyridin-4-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 172 is obtained starting from intermediates 129 and 249 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.23 (d, 1H), 7.52 (dd, 1H), 7.26 (td,1H), 7.11 (dd, 1H), 7.01 (dd, 1H), 6.85 (sl, 1H), 3.94 (m, 2H), 3.9 (s,3H), 3.53/3.34 (dd, 2H), 3.31 (m, 2H), 2.74/2.24 (2m, 2H), 2.68/2.37(2dd, 2H), 1.93/1.75 (2m, 2H), 1.86-1.66 (m, 2H), 1.41 (s, 18H), 1.36(m, 2H), 1.35 (s, 9H), 1.19 (2m, 2H), 0.69/0.61 (t, 3H)

Example 221:(3S)-3-(4-Aminobutyl)-1-{[4-fluoro-2-(2-methoxypyridin-4-yl)phenyl}-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 221 is obtained starting from intermediate 172 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.17 (d, 1H), 7.64 (dd, 1H), 7.29 (td, 1H),7.17 (dd, 1H), 7.01 (dd, 1H), 6.86 (s, 1H), 4.32 (dd, 2H), 3.9 (s, 3H),3.45/3.07 (2m, 2H), 3.17/2.84 (2m, 2H), 2.9 (m, 2H), 2.1/1.68 (2m, 2H),1.85/1.35 (2m, 2H), 1.6 (m, 2H), 1.07 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=466.1905 (466.1902)

Elemental analysis: C=56.79 (56.77); H=6.15 (6.28); N=8.94 (9.03)

RP: −9.530 (589 nm, T=19° C., C=1.0)

Example 222:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(2-oxo-1H-pyridin-4-yl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 222 is obtained starting from intermediate 172 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.64 (dd, 1H), 7.62 (d, 1H), 7.29 (td, 1H),7.18 (dd, 1H), 6.57 (d, 1H), 6.53 (dd, 1H), 4.3 (dd, 2H), 3.51/3.15 (2m,2H), 3.24/2.95 (2m, 2H), 2.92 (m, 2H), 2.13/1.7 (2m, 2H), 1.86/1.38 (2m,2H), 1.58 (m, 2H), 1.1 (m, 2H)

¹⁹F NMR: (400 MHz, D2O) δ ppm −109.6

ESI/FIA/HR and MS/MS: [M+H]+=452.1745 (452.1745)

Elemental analysis: C=56.06 (55.87); H=5.96 (6.03); N=9.21 (9.31)

RP: −10.270 (589 nm, T=19° C., C=0.9)

Intermediate 173: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-hydroxy-2-(4-methylphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 173 is obtained starting from intermediates 129 and 266 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.4 (s, 1H), 7.2 (s, 4H), 7.2 (d, 1H),6.75 (dd, 1H), 6.7 (t, 1H), 6.55 (s, 1H), 3.95 (m, 2H), 3.4 (d, 1H),3.25 (d, 1H), 2.8 (m, 3H), 2.7 (dd, 1H), 2.35 (s, 3H), 2.25 (dd, 1H),2.15 (m, 1H), 1.9 (m, 1H), 1.85-1.7 (m, 3H), 1.35 (2s, 18H), 1.25 (m,2H), 1.2 (t, 3H), 0.75 (m, 2H)

Example 223:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[4-hydroxy-2-(4-methylphenyl)-phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 223 is obtained starting from intermediate 173 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.47 (d, 1H), 7.35 (d, 2H), 7.22 (d, 2H),6.95 (dd, 1H), 6.83 (d, 1H), 4.32/4.19 (AB, 2H), 3.32/3.05 (2m, 2H),3.18/2.77 (2m, 2H), 2.95 (m, 2H), 2.38 (s, 3H), 2.09/168 (2m, 2H),1.85/1.35 (2m, 2H), 1.6 (m, 2H), 1.2-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=447.2045 (447.2043)

Elemental analysis: C=62.20 (61.87); H=6.77 (7.00); N=6.19 (6.27)

RP: −32.320 (589 nm, T=20° C., C=0.7)

Intermediate 174: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[4-methoxy-2-(imidazo[1,2-a]pyridin-3-yl)benzyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 174 is obtained starting from intermediates 129 and 267 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.98 (d, 1H), 7.66 (d, 1H), 7.63 (d,1H), 7.5 (s, 1H), 7.29 (t, 1H), 7.1 (dd, 1H), 6.98 (d, 1H), 6.9 (t, 1H),3.9 (m, 2H), 3.8 (s, 3H), 3.35 (m, 2H), 3.35/3.19 (AB, 2H), 2.7/2.25 (m,2H), 2.62/2.1 (m, 2H), 1.85/1.7 (m, 2H), 1.65 (m, 2H), 1.4 (s, 18H),1.35 (m, 2H), 1.3 (s, 9H), 1.15 (t, 3H), 0.65 (m, 2H)

Example 224:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[4-hydroxy-2-(imidazo[1,2-a]-pyridin-3-yl)benzyl]-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 224 is obtained starting from intermediate 174 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8 (d, 1H), 7.67 (s, 1H), 7.65 (d, 1H), 7.59(d, 1H), 7.42 (t, 1H), 7.09 (dd, 1H), 6.99 (t, 1H), 6.96 (df, 1H), 4.15(m, 2H), 3.4/3.02 (m, 2H), 3.02/2.72 (m, 2H), 2.9 (m, 2H), 2.1/1.6 (m,2H), 1.75/1.22 (m, 2H), 1.5 (m, 2H), 0.92 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=473.1950 (473.1948)

Elemental analysis: C=58.82 (58.47); H=6.00 (6.19); N=11.80 (11.86)

RP: −34.930 (589 nm, T=18° C., C=0.9)

Intermediate 175: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-methoxy-2-pyridin-4-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 175 is obtained starting from intermediates 129 and 268 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 8.61 (d, 2H), 7.41 (d, 2H), 7.38 (d,1H), 7 (dd, 1H), 6.8 (d, 1H), 3.92 (m, 2H), 3.79 (s, 3H), 3.49/3.3 (AB,2H), 2.73/2.18 (m, 2H), 2.73 (m, 2H), 2.67/2.3 (m, 2H), 1.95-1.8 (m,2H), 1.7 (m, 2H), 1.35 (2s, 18H), 1.22 (m, 2H), 1.18 (t, 3H), 0.69/0.55(m, 2H)

Example 225:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxy-2-pyridin-4-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 225 is obtained starting from intermediate 175 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.6 (d, 2H), 7.5 (d, 1H), 7.41 (d, 2H),7.01 (dd, 1H), 6.88 (d, 1H), 4.31/4.2 (AB, 2H), 3.41/3.05 (m, 2H),3.15/2.8 (m, 2H), 2.97 (m, 2H), 2.09/1.65 (m, 2H), 1.85/1.35 (m, 2H),1.6 (m, 2H), 1.09 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=434.1841 (434.1839)

Elemental analysis: C=58.51 (58.19); H=5.87 (6.51); N=9.77 (9.69)

RP: −28.730 (589 nm, T=18° C., C=0.6)

Intermediate 176: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[4-fluoro-2-(3-fluorophenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 176 is obtained starting from intermediates 129 and 269 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.52-7.08 (m, 7H), 3.92 (m, 2H),3.51/3.32 (AB, 2H), 3.3 (m, 2H), 2.72/2.21 (m, 2H), 2.69/2.36 (m, 2H),2-1.85 (m, 2H), 1.78 (m, 2H), 1.4 (s, 18H), 1.34 (m, 2H), 1.31 (s, 9H),1.18 (m, 3H), 0.65 (t, 2H)

¹⁹F NMR: (400 MHz, dmso-d6) δ ppm −112/−114

Example 226:(3S)-3-(4-aminobutyl)-1-[[4-fluoro-2-(3-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 226 is obtained starting from intermediate 176 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.65 (dd, 1H), 7.5 (m, 1H), 7.25 (m, 1H),7.25 (d, 1H), 7.25-7.1 (m, 3H), 4.4 (d, 1H), 4.3 (d, 1H), 3.5-3.35 (m,1H), 3.2 (m, 1H), 3.15 (m, 1H), 2.95 (m, 2H), 2.85 (dd, 1H), 2.1 (m,1H), 1.85 (m, 1H), 1.7 (m, 1H), 1.6 (in, 2H), 1.35 (m, 1H), 1.2-1 (m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=453.1748 (453.1749)

Elemental analysis: C=58.06 (58.40); H=6.00 (6.01); N=6.14 (6.19)

RP: −15.830 (589 nm, T=20.5° C., C=1.0)

Intermediate 177: tert-Butyl(3S)-3-{4-[Bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[(4-hydroxy-2-thiophen-2-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 177 is obtained starting from intermediates 129 and 255 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.55 (s, 1H), 7.55 (d, 1H), 7.25 (d,1H), 7.2 (d, 1H), 7.1 (m, 1H), 6.8 (s, 1H), 6.75 (dd, 1H), 4 (m, 2H),3.5 (d, 1H), 3.3 (d, 1H), 3.25 (m, 2H), 2.95-2.8 (m, 2H), 2.4 (dd, 1H),2.25 (m, 1H), 2.05-1.8 (m, 4H), 1.4 (s, 18H), 1.35 (s, 9H), 1.3 (m, 2H),1.2 (t, 3H), 0.65 (m, 2H)

Example 227:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxy-2-thiophen-2-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 227 is obtained starting from intermediate 177 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.55 (d, 1H), 7.45 (d, 1H), 7.2 (m, 1H),7.15 (d, 1H), 6.95 (m, 2H), 4.45 (d, 1H), 4.35 (d, 1H), 3.55-3.4 (m,1H), 3.35-3.25 (m, 1H), 3.15 (m, 1H), 2.95 (m, 2H), 2.9 (dd, 1H), 2.15(m, 1H), 1.85 (m, 1H), 1.7 (m, 1H), 1.6 (m, 2H), 1.4 (m, 1H), 1.2 (m,1H), 1.1 (m, 1H)

ESI/FIA/HR and MS/MS: [M+H]+=439.1450 (439.1451)

Elemental analysis: C=55.29 (54.78); H=6.41 (6.21); N=6.46 (6.39);S=7.06 (7.31)

RP: −36.090 (589 nm, T=20.5° C., C=1.0)

Intermediate 178: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-1-[[2-(4-fluorophenyl)-4-hydroxyphenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 178 is obtained starting from intermediates 129 and 270 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.5 (sl, 1H), 7.39 (dd, 1H), 7.24 (dd,1H), 7.2 (d, 1H), 6.75 (dd, 2H), 6.6 (d, 2H), 3.92 (m, 2H), 3.31/3.21(AB, 2H), 3.3 (m, 2H), 2.72/2.12 (2*m, 2H), 2.67/2.3 (2*m, 2H), 2-1.8(m, 2H), 1.8 (m, 2H), 1.4 (s, 18H), 1.35 (m, 2H), 1.32 (s, 9H), 1.18 (t,3H), 0.7 (m, 2H).

³¹P NMR: (400 MHz, dmso-d6) δ ppm −114.8

Example 228:(3S)-3-(4-Aminobutyl)-1-[[2-(4-fluorophenyl)-4-hydroxyphenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 228 is obtained starting from intermediate 178 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.47 (d, 1H), 7.32 (dd, 2H), 7.22 (dd, 2H),6.98 (dd, 1H), 6.85 (d, 1H), 4.32/4.2 (AB, 2H), 3.37/3.05 (m, 2H),3.15/2.8 (m, 2H), 2.95 (m, 2H), 2.09/1.65 (m, 2H), 1.85/1.35 (m, 2H),1.59 (m, 2H), 1.1 (m, 2H)

¹⁹F NMR: (400 MHz, D2O) δ ppm −113.5

ESI/FIA/HR and MS/MS: [M+H]+=451.1792 (451.1793)

Elemental analysis: C=58.29 (58.66); H=6.12 (6.27); N=6.20 (6.22)

RP: −36.630 (589 nm, T=21° C., C=1.0)

Intermediate 179: tert-Butyl(3S)-3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-1-[[2-(3,4-dimethoxyphenyl)-4-hydroxyphenyl]methyl]-4-ethoxy-4-oxo-1,4-azaphosphinane-3-carboxylate

Intermediate 179 is obtained starting from intermediates 129 and 256 inaccordance with procedure F described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.4 (m, 1H), 7.2 (d, 1H), 7 (d, 1H),6.85 (m, 2H), 6.7 (dd, 1H), 6.6 (dd, 1H), 3.95 (m, 2H), 3.8 (2s, 6H),3.4/3.25 (2d, 2H), 3.3 (m, 2H), 2.8 (m, 1H), 2.7 (m, 1H), 2.3 (dd, 1H),2.15 (m, 1H), 1.9 (m, 1H), 1.8 (m, 3H), 1.4/1.25 (2m, 2H), 1.4 (s, 18H),1.35 (s, 9H), 1.2 (t, 3H), 0.75 (quint, 2H)

Example 229:(3S)-3-(4-Aminobutyl)-1-[[2-(3,4-dimethoxyphenyl)-4-hydroxyphenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 229 is obtained starting from intermediate 179 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.05 (s, 1H), 7-6.85 (dd;d, 2H), 6.85(d, 1H), 6.25 (dd, 1H), 6.15 (s, 1H), 3.75 (s, 6H), 3.2 (d, 1H), 3.05(d, 1H), 3-2.85 (m, 1H), 2.8-2.65 (m, 1H), 2.45-2.25 (m, 3H), 2.15 (m,1H), 1.85-1.7 (m, 2H), 1.65 (m, 1H), 1.3-1.15 (m, 3H), 0.9 (m, 1H), 0.8(m, 1H)

ESI/FIA/HR and MS/MS: ESI-HR+/−:[M+H]+=493.2098 (493.2098)

Elemental analysis: C=58.52 (58.53); H=6.32 (6.75); N=5.48 (5.69)

RP: −32.470 (589 nm, T=20° C., C=0.9)

Example 230:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[(4-hydroxyphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 230 is obtained starting from intermediate 129 and4-hydroxybenzaldehyde in accordance with procedures F and D describedhereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.32 (d, 2H), 6.9 (d, 2H), centred at 4.2(AB, 2H), 3.7/3.28 (2m, 2H), 3.45/3.05 (2dd, 2H), 2.9 (m, 2H), 2.21/1.75(2m, 2H), 1.9/1.45 (2m, 2H), 1.59 (m, 2H), 1.22/1.1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=357.1577 (357.1574)

Elemental analysis: C=54.12 (53.93); H=6.96 (7.07); N=7.93 (7.86)

RP: −56.580 (589 nm, T=20° C., C=1.0)

Example 231:(3S)-3-(4-Aminobutyl)-1-[[2-(4-chlorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 231 is obtained starting from intermediate 129 and2-(4-chlorophenyl)benzaldehyde in accordance with procedures F and Ddescribed hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.59 (m, 1H), 7.51 (m, 2H), 7.51 (d, 2H),7.38 (m, 1H), 7.31 (d, 2H), 4.33 (AB, 2H), 3.39/3:08 (2m, 2H), 3.15/2.83(2m, 2H), 2.92 (m, 2H), 2.07/1.62 (2m, 2H), 1.83/1.34 (2m, 2H), 1.56 (m,2H), 1.06 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.1541 (451.1553)

Elemental analysis: C=58.91 (58.60); H=6.12 (6.26); N=5.85 (6.21)

RP: −10.140 (589 nm, T=20° C., C=0.8)

Example 232:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[2-[2-methyl-5-(trifluoromethyl)-pyrazol-3-yl]phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 232 is obtained starting from intermediate 129 and2-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzaldehyde inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.63/7.46 (m, 4H), 6.81 (s, 1H), 4.21 (AB,2H), 3.65 (s, 3H), 3.5/3.19 (2m, 2H), 3.26/3 (2m, 2H), 2.91 (m, 2H),2.15/1.69 (2m, 2H), 1.87/1.4 (2m, 2H), 1.58 (m, 2H), 1.11 (m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −61.8

ESI/FIA/HR and MS/MS: [M+H]+=489.1869 (489.1878)

Elemental analysis: C=51.64 (51.64); H=6.03 (5.78); N=11.47 (11.47)

RP: −27.030 (589 nm, T=20° C., C=0.9)

Example 233:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[[2-(trifluoromethyl)-phenyl]methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 233 is obtained starting from intermediate 129 and2-trifluoromethylbenzaldehyde in accordance with procedures F and Ddescribed hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.88-7.6 (m, 4H), 4.51 (AB, 2H), 3.69/3.43(2m, 2H), 3.48/3.25 (2m, 2H), 2.92 (m, 2H), 2.22/1.78 (2m, 2H),1.93/1.49 (2m, 2H), 1.59 (m, 2H), 1.23/1.09 (2m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −58.3

ESI/FIA/HR and MS/MS: [M+H]+=409.1492 (409.1499)

Elemental analysis: C=49.52 (50.00); H=5.85 (5.92); N=7.00 (6.86)

RP: −38.120 (589 nm, T=20° C., C=1.0

Example 234:(3S)-3-(4-Aminobutyl)-1-[4-fluoro-2-pyrimidin-5-ylphenyl)methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 234 is obtained starting from intermediate 129 and4-fluoro-(2-pyrimidin-5-yl)benzaldehyde in accordance with procedures Fand D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 9.2 (s, 1H), 8.82 (s, 2H), 7.7 (dd, 1H),7.35 (td, 1H), 7.2 (dd, 1H), 4.38/4.28 (2*d, 2H), 3.5/3.15 (2*m, 2H),3.25/2.9 (2*m, 2H), 2.9 (t, 2H), 2.1/1.6 (2*m, 2H), 1.85/1.6 (2*m, 2H),1.6/1.1 (2*m, 2H), 1.38/1.1 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=437.1740 (437.1753)

Elemental analysis: C=54.96 (55.04); H=4.82 (6.00); N=12.78 (12.84)

RP: −23.070 (589 nm, T=20° C., C=1.1)

Example 235:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[2-(2-methylpyrazol-3-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 235 is obtained starting from intermediates 129 and 280 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.7-7.35 (m, 4H), 7.65 (d, 1H), 6.45 (d,1H), 4.25/4.15 (dd, 2H), 3.6 (s, 3H), 3.5/3.2 (2m, 2H), 3.3/3 (dd, 2H),2.9 (m, 2H), 2.15/1.7 (2m, 2H), 1.9/1.4 (2m, 2H), 1.6 (m, 2H), 1.3-1 (m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=421.1998 (421.2004)

Elemental analysis: C=57.19 (57.13); H=7.08 (6.95); N=13.43 (13.33)

RP: −29.970 (589 nm, T=19.5° C., C=1.0)

Example 236:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(2-methylpyrazol-3-yl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 236 is obtained starting from intermediates 129 and 277 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7 (dd, 1H), 7.65 (d, 1H), 7.39 (td, 1H),7.24 (dd, 1H), 6.5 (d, 1H), 4.25/4.13 (AB, 2H), 3.61 (s, 3H), 3.48/3.18(m, 2H), 3.29/3 (m, 2H), 2.94 (m, 2H), 2.17/1.7 (m, 2H), 1.9/1.41 (m,2H), 1.6 (m, 2H), 1.2/1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=439.1903 (439.1905)

Elemental analysis: C=54.74 (54.79); H=6.38 (6.44); N=12.57 (12.78)

RP: −26.790 (589 nm, T=21° C., C=1.0)

Example 237:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[(2-imidazo[1,2-a]pyridin-3-ylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 237 is obtained starting from intermediates 129 and 227 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.98 (d, 1H), 7.68 (s, 1H), 7.65 (d, 1H),7.65 (m, 2H), 7.52 (m, 1H), 7.45 (dd, 1H), 7.22 (m, 1H), 6.98 (t, 1H),4.25 (m, 2H), 3.45/3.1 (2*m, 2H), 2.9 (m, 2H), 2.85 (m, 2H), 2.12/1.55(2*m, 2H), 1.8/1.55 (2*m, 2H), 1.55/0.95 (2*m, 2H), 1.28/0.95 (2*m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=457.1993 (457.1999)

Elemental analysis: C=60.73 (60.52); H=6.00 (6.40); N=12.29 (12.27)

RP: −33.550 (589 nm, T=19° C., C=0.9)

Example 238:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(3-hydroxyphenyl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 238 is obtained starting, from intermediates 129 and 254 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.6 (dd, 1H), 7.4 (m, 1H), 7.25 (m,1H), 7.15 (d, 1H), 6.95 (dd, 1H), 6.9 (dd, 1H), 6.85 (s, 1H), 4.4 (d,1H), 4.25 (d, 1H), (m, 1H), 3.25-3 (m, 2H), 2.95 (m, 2H), 2.85 (dd, 1H),2.1 (m, 1H), 1.85 (n, 1H), 1.65 (m, 1H), 1.6 (m, 2H), 1.35 (m, 1H),1.2-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.1794 (451.1793)

Elemental analysis: C=58.81 (58.66); H=5.81 (6.27); N=6.19 (6.22)

RP: −19.520 (589 nm, T=21° C., C=1.0)

Example 239:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(6-methoxypyridin-3-yl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 239 is obtained starting from intermediate 129 and4-fluoro-2-(6-methoxy-3-pyridinyl)benzaldehyde in accordance withprocedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.1 (d, 1H), 7.8 (dd, 1H), 7.65 (dd, 1H),7.3 (td, 1H), 7.15 (dd, 1H), 7 (d, 1H), 4.4/4.3 (2 d, 2H), 3.9 (s, 3H),3.45 (m, 1H), 3.2 (dd, 1H), 3.1 (m, 1H), 2.95 (m, 2H), 2.85 (dd, 1H),2.1 (m, 1H), 1.85 (m, 1H), 1.65 (m, 1H), 1.6 (m, 2H), 1.35 (m, 1H), 1.1(m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=466.1903 (466.1902)

Elemental analysis: C=57.18 (56.77); H=6.17 (6.28); N=9.05 (9.03)

RP: −11.850 (589 nm, T=20° C., C=0.9)

Example 240:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[2-(6-hydroxypyridin-3-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 240 is obtained starting from intermediate 129 and2-(6-methoxy-3-pyridinyl)benzaldehyde in accordance with procedures Fand D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7 (dd, 1H), 7.6 (d, 1H), 7.55-7.4 (2m,4H), 6.7 (d, 1H), 4.4 (2 d coal., 2H), 3.5 (m, 1H), 3.3 (dd, 1H), 3.2(m, 1H), 3 (dd, 1H), 2.95 (m, 2H), 2.1 (m, 1H), 1.9 (m, 1H), 1.7 (m,1H), 1.6 (m, 2H), 1.4 (m, 1H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=434.1840 (434.1839)

Elemental analysis: C=58.14 (58.19); H=6.38 (6.51); N=9.60 (9.69)

RP: −8.440 (589 nm, T=20° C., C=0.8)

Example 241:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(6-hydroxypyridin-3-yl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 241 is obtained starting from intermediate 129 and4-fluoro-2-(6-methoxy-3-pyridinyl)benzaldehyde in accordance withprocedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7 (dd, 1H), 7.6 (m, 2H), 7.3 (td, 1H),7.2 (dd, 1H), 6.7 (d, 1H), 4.35 (2 d coal., 2H), 3.5 (m, 1H), 3.25 (m,1H), 3.2 (m, 1H), 3 (dd, 1H), 2.95 (m, 2H), 2.1 (m, 1H), 1.9 (m, 1H),1.7 (m, 1H), 1.6 (quint, 2H), 1.4 (m, 1H), 1.1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=452.1746 (452.1745)

Elemental analysis: C=55.62 (55.87); H=5.85 (6.03); N=9.16 (9.31)

RP: −7.630 (589 nm, T=20° C., C=0.7)

Example 242:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[4-hydroxy-2-(6-methoxypyridin-3-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 242 is obtained starting from intermediates 129 and 230 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.95 (d, 1H), 7.6 (dd, 1H), 7.4 (d, 1H),6.9 (m, 2H), 6.7 (d, 1H), 4.2-4.1 (2d, 2H), 3.8 (s, 3H), 3.3-2.95 (2m,2H), 3.1-2.7 (2m, 2H), 2.85 (m, 2H), 2.0-1.5 (2m, 2H), 1.75-1.25 (2m,2H), 1.5 (m, 2H), 1.0 (m, 2H)

Elemental analysis: C=56.79 (57.01); H=6.62 (6.52); N=8.99 (9.07)

RP: −27.320 (589 nm, T=20° C., C=0.8)

Example 243:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-oxo-1,3-dihydrobenz-imidazol-5-yl)methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 243 is obtained starting from intermediate 129 and2-oxo-1,3-dihydrobenzothiazole-5-carbaldehyde in accordance withprocedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.25 (s, 1H), 7.2 (m, 2H), 4.45 (d, 1H),4.25 (d, 1H), 3.8-3.65 (m, 1H), 3.55-3.4 (m, 1H), 3.35 (m, 1H), 3.1 (dd,1H), 2.95 (m, 2H), 2.3-2.15 (m, 1H), 2-1.85 (m, 1H), 1.85-1.7 (m, 1H),1.6 (m, 2H), 1.55-1.4 (m, 1H), 1.3-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=397.1635 (397.1635)

Example 244:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(6-methoxypyridin-2-yl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 244 is obtained starting from intermediates 129 and 231 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 8.2 (t, 1H), 7.8 (dd, 1H), 7.7 (dd, 1H),7.55 (m, 2H), 7.2 (d, 1H), 4.7 (d, 1H), 4.5 (d, 1H), 4.2 (s (+m, 3H),3.9 (m, 1H), 3.6 (m, 3H), 3.2 (t (+m, 2H), 2.6 (m, 1H), 2.05 (m, 2H),1.8 (m, 2H), 1.7 (m, 1H), 1.4/1.3 (2m, 2H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −110.9

ESI/FIA/HR and MS/MS: [M+H]+=466.1901 (466.1902)

Elemental analysis: C=57.09 (56.77); H=6.16 (6.28); N=8.87 (9.03)

RP: −69.790 (589 nm, T=19° C., C=0.8)

Example 245:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(1,3-thiazol-2-yl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 245 is obtained starting from intermediates 129 and 232 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 8 (d, 1H), 7.7 (m, 2H), 7.7 (dd, 1H), 7.3(td, 1H), 4.5 (d, 1H), 4.3 (d, 1H), 3.85 (m, 1H), 3.45 (m, 2H), 3.15(dd, 1H), 2.9 (m, 2H), 2.3 (m, 1H), 1.85 (m, 2H), 1.55 (m, 3H), 1.2 (m,1H), 1 (m, 1H)

¹⁹F NMR: (300 MHz, D2O) δ ppm −109

ESI/FIA/HR and MS/MS: [M+H]+=442.1358 (442.1360)

Elemental analysis: C=51.13 (51.69); H=5.30 (5.71); N=9.42 (9.52);S=7.25 (7.26)

RP: −99.540 (589 nm, T=18° C., C=0.8)

Example 246:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[4-hydroxy-2-(3-methylimidazol-4-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid, Hydrobromide

Example 246 is obtained starting from intermediates 129 and 276 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 8.85 (s, 1H), 7.65 (d, 1H), 7.6 (s, 1H),7.2 (dd, 1H), 7 (d, 1H), 4.4 (m, 1H), 4.15 (m, 1H), 3.7 (m, 1H), 3.6 (s,3H), 3.55-3.2 (2m, 2H), 3.1 (m, 1H), 2.9 (m, 2H), 2.15 (m, 1H), 1.9 (m,2H), 1.6 (m, 3H), 1.25 (2 m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=437.1947 (437.1948)

Elemental analysis: C=39.13 (40.15); H=5.22 (5.22); N=8.85 (9.37)

RP: −15.390 (589 nm, T=21° C., C=1.0).

Example 247:(3S)-3-(4-Aminobutyl)-4-hydroxy-1-[[4-hydroxy-2-(2-methylpyrazol-3-yl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 247 is obtained starting from intermediate 129 and4-hydroxy-2-(2-methylpyrazol-3-yl)benzaldehyde in accordance withprocedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.63 (s, 1H), 7.52 (dd, 1H), 7.08 (d, 1H),6.9 (s, 1H), 6.44 (d, 1H), 4.18/4.05 (2m, 2H), 3.61 (s, 3H), 3.45/3.15(2m, 2H), 3.26/2.95 (2dd, 2H), 2.95 (m, 2H), 2.15/1.68 (2m, 2H), 1.9/1.4(2m, 2H), 1.6 (m, 2H), 1.2/1.1 (2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=437.1947 (437.1948)

Elemental analysis: C=55.22 (55.04); H=6.48 (6.70); N=12.72 (12.84)

RP: −44.210 (589 nm, T=20° C., C=1.0)

Example 248:(3S)-3-(4-Aminobutyl)-1-[[2-(3,4-dimethoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 248 is obtained starting from intermediate 129 and2-(3,4-dimethoxyphenyl)benzaldehyde in accordance with procedures F andD described hereinbefore.

¹H NMR: (300 MHz, D2O) δ ppm 7.6 (dd, 1H), 7.5 (m, 2H), 7.35 (dd, 1H),7.1 (d, 1H), 7 (d, 1H), 6.9 (dd, 1H), 4.45/4.3 (2 d, 2H), 3.85 (2 s,6H), 3.35/3.1 (2 m, 2H), 3.1/2.9 (m+dd, 2H), 2.95 (m, 2H), 2.1/1.65 (2m, 2H), 1.85/1.35 (2m, 2H), 1.6 (m, 2H), 1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=477.2147 (477.2149)

Elemental analysis: C=60.13 (60.50); H=6.84 (6.98); N=5.68 (5.88)

RP: −21.710 (589 nm, T=18° C., C=1.0)

Example 249:(3S)-3-(4-Aminobutyl)-1-[[2-(2,3-dimethylimidazol-4-yl)-4-hydroxy-phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 249 is obtained starting from intermediates 129 and 275 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.55 (d, 1H), 7.45 (s, 1H), 7.15 (dd, 1H),6.95 (s, 1H), 4.15 (sl, 2H), 3.65-3.5 (m, 1H), 3.45 (s, 3H), 3.35 (m,1H), 12 (m, 1H), 2.95 (dd, 1H), 2.95 (t, 2H), 2.65 (s, 3H), 2.15 (m,1H), 1.9 (m, 1H), 1.75 (m, 1H), 1.6 (m, 2H), 1.45 (m, 1H), 1.35-1.05(2m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=451.2102 (451.2105)

Elemental analysis: C=46.98 (47.47); H=6.05 (6.07); N=10.40 (10.54)

RP: −37.730 (589 nm, T=20.5° C., C=1.0)

Example 250:(3S)-3-(4-Aminobutyl)-1-[[2-(2,3-dimethylimidazol-4-yl)phenyl]-methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 250 is obtained starting from intermediates 129 and 226 inaccordance with procedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.75-7.45 (m, 4H), 7.45 (s, 1H), 4.25 (m,2H), 3.5/3.2 (2m, 2H), 3.4/3.1 (m, 2H), 3.4 (s, 3H), 2.9 (m, 2H), 2.65(s, 3H), 2.1/1.7 (2m, 2H), 1.9/1.45 (2m, 2H), 1.6 (m, 2H), 1.25/1.1 (2m,2H)

ESI/FIA/HR and MS/MS: [M+H]+=435.2179 (435.2161)

Elemental analysis: C=49.57 (50.37); H=5.92 (5.88); N=9.92 (10.21)

RP: −23.310 (589 nm, T=20° C., C=0.9)

Example 251:(3S)-3-(4-Aminobutyl)-1-[[4-fluoro-2-(4-fluoro-3-hydroxyphenyl)-phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicAcid

Example 251 is obtained starting from intermediate 129 and4-fluoro-2-(4-fluoro-3-hydroxyphenyl)benzaldehyde in accordance withprocedures F and D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.6 (d, 1H), 7.25 (2*m, 2H), 7.15 (d, 1H),6.95 (d, 1H), 6.8 (m, 1H), 4.4 (d, 1H), 4.3 (d, 1H), 3.5-3.35 (m, 1H),3.2-3:05 (m, 2H), 2.95 (m, 2H), 2.85 (dd, 1H), 2.1 (m, 1H), 1.85 (m,1H), 1.65 (m, 1H), 1.6 (m, 2H), 1.35 (m, 1H), 1.2-1 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=469.1696 (469.1698)

Elemental analysis: C=56.82 (56.41); H=5.77 (5.81); N=6.02 (5.98)

RP: −12.950 (589 nm, T=21° C., C=1.0)

Example 252:(3S)-3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-pyridin-4-ylphenyl)-methyl]-1,4-azaphosphinane-3-carboxylicAcid

Example 252 is obtained starting from intermediate 129 and2-(4-pyridyl)benzaldehyde in accordance with procedures F and Ddescribed hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 8.6 (d, 2H), 7.64 (m, 1H), 7.57 (m, 2H),7.42 (d, 2H), 7.41 (m, 1H), 4.42/4.3 (dd, 2H), 3.44/3.09 (dd, 2H),3.18/2.88 (dd, 2H), 2.93 (m, 2H), 2.09/1.64 (2*m, 2H), 1.85/1.35 (2*m,2H), 1.59 (m, 2H), 1.08 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=418.1897 (418.1895)

Elemental analysis: C=61.00 (60.42); H=6.62 (6.76); N=10.20 (10.07)

RP: −17.980 (589 nm, T=28° C., C=0.9)

Procedure H: Synthesis of the Azaphosphepanes

A solution of N-Boc allylamine (30 g, 190 mmol) in THF (170 mL) is addeddropwise to a 60% NaH suspension (11.45 g, 285 mmol, 1.5 eq) in THF (100mL) and under an argon atmosphere. The mixture is left in contact for 1hour 30 minutes, and then benzyl bromide (34 mL, 285 mmol, 1.5 eq) insolution in THF (30 mL) is added. The reaction mixture is stirred atambient temperature for 48 hours. The THF is evaporated off underreduced pressure and the evaporate is taken up in DCM (10 mL) cooled inan ice-water bath and then poured slowly onto H₂O (100 mL). The organicphase is separated off, and the aqueous phase is re-extracted with DCM(2×100 mL). The combined organic phases are washed with H₂O (2×50 mL),dried over MgSO₄ and then evaporated. The residue obtained is purifiedby flash chromatography on silica gel using as eluant a heptane/DCMgradient (from 50:50 to 0:100). Intermediate 180 is obtained in the formof a colourless oil (39.8 g, 160.92 mmol) with a yield of 85%.

¹H NMR: (400 MHz, DMSO-d6) δ ppm 7.65 (t, 2H), 7.22 (m, 3H), 5.75 (m,1H), 5.1 (m, 2H), 4.33 (s, 2H), 3.75 (m, 2H), 1.39 (s, 9H)

Tetraethoxysilane (38.35 mL, 173 mmol, 2 eq) is added dropwise to asolution of hypophosphorous acid (11.42 g, 173 mmol, 2 eq) inacetonitrile (224 mL) at 0° C. and under an argon atmosphere. Afterreturning to ambient temperature, there are added to the reactionmixture (degassed with argon) intermediate 180 (21.4 g, 86.5 mmol) insolution in MeCN (44.7 mL), Xantphos (0.55 g, 11 mmol) and then Pd₂dba₃(0.396 g, 5 mmol). The mixture is heated at reflux for 16 hours. Afterconcentration under reduced pressure, the residue obtained is purifiedby flash chromatography on silica gel using as eluant an AcOEt/EtOHgradient (from 95:5 to 90:10). Intermediate 181 is obtained in the formof a colourless oil (10.1 g, 29.58 mmol) with a yield of 34%.

¹H NMR: (400 MHz, DMSO-d6) δ ppm 7.32 (t, 2H), 7.22 (m, 3 FI), 6.95 (d,1H), 4.38 (s, 2H), 3.99 (m, 2H), 3.19 (m, 2H), 1.65 (m, 4H), 1.4 (m,9H), 1.21 (t, 3H)

³¹P NMR: (400 MHz, DMSO-d6) δ ppm 40.7

A solution of 1M LiHMDS in THF (29.6 mL, 29.6 mmol, 1 eq) is added to asolution of intermediate 181 (10.1 g, 29.6 mmol) in THF (100 mL)previously degassed with argon. After stirring for 30 minutes at −70°C., allyl bromide (2.56 mL, 29.6 mmol, 1 eq) is added. The reactionmixture is stirred for 2 hours at ambient temperature and then pouredonto a saturated aqueous NH₄Cl solution. The mixture is extracted withDCM (3×100 mL), and the organic phase is washed with H₂O (2×100 mL) anddried over Na₂SO₄. After concentration under reduced pressure, theresidue obtained is purified by flash chromatography on silica gel usingas eluant an AcOEt/EtOH gradient (from 100%-90:10). The expectedintermediate 182 is obtained in the form of a colourless oil (9.3 g,24.3 mmol) with a yield of 82%.

¹H NMR: (400 MHz, DMSO-d6) δ ppm 7.4-7.2 (m, 5H), 5.2 (m, 1H), 5.18(2dd, 2H), 4.4 (s, 2H), 3.91 (quad, 2H), 3.15 (m, 2H), 2.6 (dd, 2H), 1.6(m, 4H), 1.4 (sl, 9H), 1.2 (t, 3H)

A 4% solution of OsO₄ in H₂O (4.64 mL, 0.73 mmol) at ambient temperatureis added dropwise to a solution of intermediate 182 (9.3 g, 24.3 mmol)and 4-methylmorpholine N-oxide (3.14 g, 26.7 mmol, 1.1 eq) in 100 mL ofan acetone/H₂O mixture (2:1). The reaction mixture is stirred at ambienttemperature for 16 hours and then poured onto a 10% solution of sodiummetabisulphite in H₂O (100 mL). The mixture is extracted with AcOEt(2×100 mL). The organic phases are combined and washed with H₂O (1×100mL), dried over MgSO₄ and then concentrated in vacuo. Intermediate 183(9.8 g, 23.58 mmol) is obtained without further purification in the formof a dark-coloured oil with a yield of 97%.

¹H NMR: (400 MHz, DMSO-d6) δ ppm 7.35-7.2 (m, 5H), 4.8/4.78 (2d, 1H),4.65 (2t, 1H), 4.36 (s, 2H), 3.9 (m, 2H), 3.75 (m, 1H), 3.35-3.2 (m,2H), 3.15 (m, 2H), 1.9/1.7 (m, 2H), 1.63 (m, 4H), 1.4 (m, 9H), 1.17 (t,3H)

³¹P NMR: (400 MHz, DMSO-d6) δ ppm 58.6/57.7

Sodium periodate (20.16 g, 94.25 mmol, 4 eq) is added in portions to asolution of intermediate 183 (9.79 g, 23.5 mmol) in 320 mL of a THF/H₂Omixture (3:1) at ambient temperature. Stirring is maintained for 72hours at ambient temperature. The reaction mixture is then extractedwith AcOEt (2×150 mL), and the organic phases are combined and washedwith H₂O (1×100 mL), dried over MgSO₄ and then concentrated in vacuo.Intermediate 184 (8.13 g, 21.2 mmol) is obtained without furtherpurification in the form of an oil with a yield of 90%.

¹H NMR: (400 MHz, dmso-d6) δ ppm 9.6 (m, 1H), 7.35-7.2 (m, 5H), 4.38 (s,2H), 4-3.75 (m, 2H), 3.25 (dd, 2H), 3.15 (m, 2H), 1.65 (m, 4H), 1.4 (m,9H), 1.2 (m, 3H)

A solution of intermediate 184 (8.13 g, 21.2 mmol) in 2N HCl (53 mL, 106mmol, 5 eq) is stirred for 4 hours at ambient temperature. The reactionmixture is concentrated in vacuo to yield intermediate 185, which isused directly without being purified further. Intermediate 185 isdissolved in DCM (150 mL) and stirred for 1 hour with MgSO₄ (10 g).NaBH(OAc)₃ (6.75 g, 31.8 mmol, 1.5 eq) is then added in portions at 0°C., and the reaction mixture is stirred at ambient temperature for 16hours. After filtering off the insoluble components, the organic phaseis washed with a 10% saturated aqueous NaHCO₃ solution (2×100 mL) andthen with H₂O (1×100 mL), and dried over MgSO₄. After concentrationunder reduced pressure, the residue obtained is purified by flashchromatography on silica gel using as eluant a DCM/EtOH gradient (98:2to 94:6). The expected product is obtained in the form of a colourlessoil (1.9 g, 7.1 mmol) with a yield of 33%.

¹H NMR: (400 MHz, DMSO-d6) δ ppm 7.3 (m, 5H), 3.9 (quadd, 2H), 3.7 (s,2H), 2.7 (m, 4H), 2-1.6 (m, 6H), 1.2 (t, 3H)

³¹P NMR: (400 MHz, DMSO-d6) δ ppm 62

2N LDA in THF (5.33 mL, 10.6 mmol, 1.5 eq) is added dropwise to asolution of intermediate 186 (1.9 g, 7.1 mmol) in THF (18 mL) at −78° C.under an argon atmosphere. After 30 minutes, di-tert-butyl dicarbonate(2.17 g, 9.95 mmol, 1.4 eq) dissolved in THF (9 mL) is added. Thereaction mixture is stirred for 1 hour 30 minutes, the temperature beingmaintained at −78° C. A further 1.5 eq of 2N LDA in THF (5.33 mL, 10.6mmol) is added dropwise. After 2 hours, the reaction mixture ishydrolysed while cold with an aqueous NH₄Cl solution (10 mL) followed byAcOEt (10 mL). After returning to ambient temperature, the reactionmixture is extracted with AcOEt (2×100 mL). The organic phases arecombined, washed with H₂O (100 mL), dried over MgSO₄ and thenconcentrated in vacuo. The residue obtained is purified by flashchromatography on silica gel using as eluant an AcOEt/THF gradient (from100% to 70:30). The expected intermediates 187 and 188 are obtained inthe form of an oily mixture (1.7 g, 4.62 mmol) with a yield of 63%.

60% NaH (0.287 g, 7.18 mmol, 1.6 eq) is added, at 10° C. and inportions, to a solution of intermediate 204 (1.74 g, 4.94 mmol, 1.1 eq)in DMSO (10 mL) under argon. Intermediates 187 and 188 (1.65 g, 4.49mmol) in solution in DMSO (5.9 mL) are then added to the suspension andthe mixture is stirred for 6 hours at ambient temperature. The reactionmixture is then hydrolysed with an aqueous NH₄Cl solution (30 mL) andextracted with AcOEt (2×50 mL). The organic phase is washed with H₂O(2×50 mL), dried over MgSO₄ and concentrated in vacuo. The residueobtained is purified by flash chromatography on silica gel using aseluant a DCM/AcOEt gradient (90:10 to 50:50). Intermediate 189 (0.342 g,0.54 mmol) and intermediate 190 (1 g, 1.6 mmol) are obtained in the formof a mixture of diastereoisomers with a yield of 36% and 12%,respectively.

Example 253:5-(4-Aminobutyl)-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphepane-5-carboxylicAcid

TMSBr (0.87 mL, 6.6 mmol, 12 eq) is added dropwise to a solution ofintermediate 189 (0.342 g, 0.54 mmol) in DCM (4 mL) under argon and atambient temperature. The mixture is stirred for 16 hours at ambienttemperature and then concentrated in vacuo. The residue is taken up inMeOH (20 mL) and stirred for 20 minutes at ambient temperature, beforebeing evaporated to dryness. The evaporate is dissolved in DCM (4 mL),and trifluoroacetic acid (0.81 mL, 10.9 mmol, 20 eq) is added. Thereaction mixture is stirred for 10 hours at ambient temperature and thenconcentrated in vacuo. The residue obtained is purified by reverse-phasechromatography using as eluant an H₂O/MeCN gradient. Example 253 (0.11g, 0.31 mmol) is obtained in the form of a white solid with a yield of57%.

¹H NMR: (400 MHz, D2O) δ ppm 7.42 (s, 5H), 4.32 (AB, 2H), 3.5-3.2 (m,4H), 2.9 (m, 2H), 2.1-1 (m, 10H)

³¹P NMR: (400 MHz, D2O) δ ppm 40.25

ESI/FIA/HR and MS/MS: [M+H]+=355.1780 (355.1786)

Elemental analysis: C=57.16 (57.62); H=7.28 (7.68); N=7.83 (7.90)

Example 254:3-(4-Aminobutyl)-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphepane-3-carboxylicAcid

TMSBr (2.53 mL, 19.2 mmol, 12 eq) is added dropwise to a solution ofintermediate 190 (1 g, 1.61 mmol) in solution in DCM (5 mL) under argonand at ambient temperature. The mixture is stirred for 16 hours atambient temperature and then concentrated in vacuo. The residue is takenup in MeOH (20 mL) and stirred for 20 minutes at ambient temperature,before being evaporated to dryness. The evaporate is dissolved in DCM (4ml), and trifluoroacetic acid (2.37 mL, 32 mmol, 20 eq) is added. Thereaction mixture is stirred for 10 hours at ambient temperature and thenconcentrated in vacuo. The residue obtained is purified by reverse-phasechromatography using as eluant an H₂O/MeCN gradient. Example 254 (0.34g, 0.96 mmol) is obtained in the form of a white solid with a yield of60%.

¹H NMR: (400 MHz, D2O) δ ppm 7.5 (m, 5H), 4.35 (m, 2H), 3.75-3.1 (m,4H), 2.95 (t, 2H), 2.15-1.4 (m, 4H), 2.1 (m, 2H), 1.6 (m, 2H), 1.35/1.2(m)+(m, 1+1H)

ESI/FIA/HR and MS/MS: [M+H]+=355.1780 (355.1786)

Elemental analysis: C=57.16 (57.62); H=7.28 (7.68); N=7.83 (7.90)

Example 255:5-(5-Aminopentyl)-1-benzyl-4-hydroxy-4-oxo-1,4-azaphosphepane-5-carboxylicAcid

Example 255 is obtained in accordance with procedure H describedhereinbefore, replacing intermediate 204 by intermediate 206.

¹H NMR: (500 MHz, D2O) δ ppm 7.54 (m, 5H), 4.41/434 (d)+(d, 1+1H),3.7/3.63 (m)+(m, 1+1H), 3.51/3.22 (m)+(m, 1+1H), 2.99 (t, 2H), 2.16/1.58(m)+(m, 1+1H), 2.14/1.51 (m)+(m, 1+1H), 2.11/1.82 (m)+(m, 1+1H), 1.67(quint., 2H), 1.39 (quint., 2H), 1.35/1.18 (m)+(m, 1+1H)

¹³C NMR: (500 MHz, D2O) δ ppm 129.4, 61, 54.7, 51.8, 39.1, 32.3, 29.4,26, 26, 25.8, 23.

³¹P NMR: (500 MHz, D2O) δ ppm 37

ESI/FIA/HR and MS/MS: [M+H]+=369.1955 (369.1943)

Elemental analysis: C=58.53 (58.68); H=7.80 (7.93); N=7.51 (7.60)

Intermediate 191: tert-Butyl5-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(3-phenylphenyl)methyl]-1,4-azaphosphepane-5-carboxylate

Intermediate 191 is obtained in accordance with procedure H describedhereinbefore, replacing benzyl bromide by 3-phenylbenzyl bromide.

¹H NMR: (400/500 MHz, dmso-d6) δ ppm 7.65 (d, 2H), 7.63 (t, 1H), 7.59(s, 1H), 7.53 (d, 1H), 7.46 (t, 2H), 7.41 (t, 1H), 7.31 (d, 1H), 4.06(m, 2H), 3.69/3.63 (2*d, 2H), 3.44 (t, 2H), 2.83/2.71 (2*m, 2H),2.8/2.67 (2*m, 2H), 2.21/1.6 (2*m, 2H), 2.12/1.88 (2*m, 2H), 1.9/1.67(2*m, 2H), 1.42 (m, 2H), 1.41 (s, 18H), 1.39 (s, 9H), 1.22 (t, 3H),1.22/0.99 (2*m, 2H)

¹³C NMR: (400/500 MHz, dmso-d6) δ ppm 129.1, 128.9, 127.9, 127.6, 127,126.7, 125.4, 61.5, 603, 50.8, 48.2, 45.8, 31.2, 31.2, 29, 28.3, 28, 28,21.6, 16.6

Example 256:5-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(3-phenylphenyl)methyl]-1,4-azaphosphepane-5-carboxylicAcid

Example 256 is obtained starting from intermediate 191 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.8-7.4 (m, 9H), 4.45/4.35 (d, 2H), 3.7-3.2(m, 4H), 2.95 (m, 2H), 2.2-1.75 (m, 4H), 1.6-1.2 (m, 6H)

³¹P NMR: (400 MHz, D2O) δ ppm 86

ESI/FIA/HR and MS/MS: [M+H]+=431.2092 (431.2094)

Elemental analysis: C=63.35 (64.17); H=6.85 (7.26); N=6.42 (6.51)

Intermediate 192: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(3-phenylphenyl)methyl]-1,4-azaphosphepane-3-carboxylate

Intermediate 192 is obtained in accordance with procedure H describedhereinbefore, replacing benzyl bromide by 3-phenylbenzyl bromide.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.7 (s, 1H), 7.66 (d, 2H), 7.5 (t, 1H),7.42 (t, 2H), 7.35 (m, 2H), 7.32 (t, 1H), 4.06 (m, 2H), 4.01/3.8 (2*d,2H), 3.45 (t, 2H), 3.32/2.76 (dd, 2H), 2.62-2.45 (m, 2H), 2-1.3 (m, 8H),1.4/1.1 (2*m, 2H), 1.4 (s, 27H), 1.25 (t, 3H)

Example 257:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(3-phenylphenyl)methyl]-1,4-azaphosphepane-3-carboxylicAcid

Example 257 is obtained starting from intermediate 192 in accordancewith method D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.8-7.4 (m, 9H), 4.45/4.35 (d, 2H),3.6-3.25 (m, 4H), 2.8 (m, 2H), 2.1-1.9 (m, 4H), 1.75-1.1 (m, 6H)

³¹P NMR: (400 MHz, D2O) δ ppm 86

ESI/FIA/HR and MS/MS: [M+H]+=431.2095 (431.2094)

Elemental analysis: C=63.89 (64.17); H=6.92 (7.26); N=6.50 (6.51)

Intermediate 193: tert-Butyl3-{4-bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(4-phenylphenyl)methyl]-1,4-azaphosphepane-3-carboxylate

Intermediate 193 is obtained in accordance with procedure H describedhereinbefore, replacing benzyl bromide by 4-phenylbenzyl bromide.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.7-7.55 (2d, 4H), 7.5 (m, 2H), 7.45(d, 2H), 7.35 (m, 1H), 4.1 (m, 2H), 3.95 (d, 1H), 3.8 (d, 1H), 3.45 (t,2H), 3.3 (m, 1H), 2.8 (m, 1H), 2.55 (m, 1H), 2-1.35 (m, 9H), 1.4 (3s,27H), 1.25 (t, 3H), 1.25 (m, 1H), 1.1 (m, 1H)

Example 258:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(4-phenylphenyl)methyl]-1,4-azaphosphepane-3-carboxylicAcid

Example 258 is obtained starting from intermediate 193 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7 (2d, 4H), 7.5 (t+d, 4H), 7.4 (td, 1H),4.35 (2d, 2H), 3.5-3.2 (m, 4H), 2.85 (m, 2H), 2.15-1 (m, 10H)

ESI/FIA/HR and MS/MS: ESI-HR +/−: [M+H]+=431.2093 (431.2094)

Elemental analysis: C=63.92 (64.17); H=7.15 (7.26); N=6.47 (6.51)

Intermediate 62: tert-Butyl5-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(4-phenylphenyl)methyl]-1,4-azaphosphepane-5-carboxylate

Intermediate 62 is obtained in accordance with procedure H describedhereinbefore, replacing benzyl bromide by 4-phenylbenzyl bromide.

Example 259:5-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(4-phenylphenyl)methyl]-1,4-azaphosphepane-5-carboxylicAcid

Example 259 is obtained starting from intermediate 62 in accordance withprocedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.75 (d, 2H), 7.7 (d, 2H), 7.6 (d, 2H), 7.5(m, 2H), 7.45 (m, 1H), 4.45/4.35 (2d, 2H), 3.75-3.1 (m, 4H), 2.95 (t,2H), 2.2-1.85 (m, 3H), 1.8 (m, 1H), 1.7-1.05 (m, 6H)

ESI/FIA/HR and MS/MS: EI-HR: [M+H]+=431.2093 (431.2094)

Elemental analysis: C=64.46 (64.17); H=7.17 (7.26); N=6.46 (6.51)

Intermediate 194: tert-Butyl3-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-phenylphenyl)methyl]-1,4-azaphosphepane-3-carboxylate

Intermediate 194 is obtained in accordance with procedure H describedhereinbefore, replacing benzyl bromide by 2-phenylbenzyl bromide.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.88 (d, 1H), 7.48-7.2 (m, 5H), 735 (m,2H), 7.15 (d, 1H), 4.05 (m, 2H), 3.9/3.7 (2*d, 2H), 3.42 (t, 2H),3.2/2.65 (dd, 2H), 2.33 (m, 2H), 2-1.5 (m, 6H), 1.42 (s, 18H), 1.4 (m,2H), 1.4 (s, 9H), 1.25 (t, 3H), 1.15/1 (2*m, 2H)

Example 260:3-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-phenylphenyl)methyl]-1,4-azaphosphepane-3-carboxylicAcid

Example 260 is obtained starting from intermediate 194 in accordancewith procedure D described hereinbefore.

¹H NMR: (400 MHz, D2O) δ ppm 7.7-7.3 (m, 9H), 4.45 (d, 1H), 4.4 (d, 1H),3.25-3 (m, 4H), 2.95 (q, 2H), 1.95-1.5 (m, 5H), 1.65 (m, 2H), 1.35 (m,1H), 1.3-1.05 (m, 2H)

ESI/FIA/HR and MS/MS: [M+H]+=431.2094 (431.2094)

Elemental analysis: C=63.81 (64.17); H=7.03 (7.26); N=6.45 (6.51)

Intermediate 67: tert-Butyl5-{4-[bis(tert-butoxycarbonyl)amino]butyl}-4-ethoxy-4-oxo-1-[(2-phenylphenyl)methyl]-1,4-azaphosphepane-5-carboxylate

Intermediate 67 is obtained in accordance with procedure H describedhereinbefore, replacing benzyl bromide by 2-phenylbenzyl bromide.

Example 261:5-(4-Aminobutyl)-4-hydroxy-4-oxo-1-[(2-phenylphenyl)methyl]-1,4-azaphosphepane-5-carboxylicAcid

Example 261 is obtained starting from intermediate 67 in accordance withprocedure D described hereinbefore.

¹H NMR: (300/500 MHz, D2O) δ ppm 7.63/7.61 (m, 1H), 7.54-7.45 (m, 4H),7.44 (m, 1H), 7.38 (m, 1H), 7.33/7.31 (m, 2H), 4.38 (m, 2H), 3.48-2.77(m, 4H), 2.94 (m, 2H), 2.05/1.42 (m, 2H), 2.03/1.43 (m, 2H), 2.01/1.66(m, 2H), 1.6 (m, 2H), 1.33/1.14 (m, 2H)

¹³C NMR: (300/500 MHz, D2O) δ ppm 178.5, 143.3, 130.4, 129.4, 129.3,129.2, 128.7, 127.7, 57.8, 55.1/51.6, 38.8, 31.7, 28.9, 26.3, 25.9, 20.5

³¹P NMR: (300/500 MHz, D2O) δ ppm 36.5

ESI/FIA/HR and MS/MS: [M+H]+=431.2095 (431.2094)

Elemental analysis: C=63.81 (64.17); H=7.14 (7.26); N=6.45 (6.51)

Preparation of Example 262

Allyl alcohol (15.27 mL, 224 mmol, 8 eq), triethylborane (6.4 mL, 6.39mmol, 0.23 eq) and tributylphosphorus (1.17 mL, 5.6 mmol, 0.2 eq) areadded in succession to a solution, degassed with argon for 30 minutes,of benzylamine (3 g, 28 mmol) and palladium acetate (0.31 g, 1.4 mmol)in THF (64 mL). The reaction mixture is degassed for 15 minutes withargon and heated at 70° C. for 20 hours. The mixture is concentratedunder reduced pressure. The residue obtained is, purified by flashchromatography on silica gel using a DCM/AcOEt gradient (from 100% to95:5) as eluant. Intermediate 195 (3.45 g, 18.4 mmol) is obtained in theform of an oil with a yield of 66%.

¹H NMR: (400 MHz, CDCl₃) δ ppm 7.3 (m, 5H), 5.9 (m, 2H), 5.15 (m, 4H),3.6 (s, 2H), 3.1 (s, 4H)

A solution of diisopropylamino-phosphorus dichloride (4.96 g, 24.6 mmol,2 eq) in DCM (41.5 mL) is added to a suspension of aluminium chloride(3.27 g, 24.6 mmol, 2 eq) in DCM (41.5 mL) at −20° C. and under an argonatmosphere. The mixture is stirred for 1 hour at ambient temperature andthen cooled to −20° C., and intermediate 195 (2.3 g, 12.3 mmol) insolution in 10 mL of DCM is then added. The reaction mixture is stirredfor 16 hours at ambient temperature and then heated for 1 hour atreflux. A solution (25 mL, 1:1) of EDTA (0.2M in H₂O) and NaHCO₃ (10% inH₂O) is then added 0° C., and the mixture is stirred for 16 hours atambient temperature. The reaction mixture is then added to 100 mL of DCMcooled by an ice bath and rendered basic with a saturated Na₂CO₃solution. The organic phase is separated off and washed with H₂O (2×50mL), dried over MgSO₄ and concentrated in vacuo. The residue obtained ispurified by flash chromatography on a silica column using as eluant anAcOEt/THF gradient (from 100% to 95:5). Intermediate 196 (2.3 g, 6.8mmol) is obtained in the form of an oil with a yield of 54%.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.3 (m, 5H), 3.52 (2s, 2H), 3.33 (m,2H), 2.78/2.6 (m, 2H), 2.62 (m, 2H), 2.3 (m, 2H), 1.99/1.72 (m, 2H), 1.4(m, 2H), 1.17 (2d, 12H)

³¹P NMR: (400 MHz, DMSO-d6) δ ppm 69.2/66.9

A solution of 2N LDA in THF (4.81 mL, 9.6 mmol, 1.4 eq) is added to asolution of intermediate 196 (2.3 g, 6.87 mmol) in THF (16.5 mL) at −70°C. and under an argon atmosphere. After stirring for 15 minutes at −70°C., a solution of (Boc)₂O (2.1 g, 9.6 mmol, 1.4 eq) in THF (5 mL) isadded dropwise, and stirring is maintained for 90 minutes at −70° C. Afurther 1.4 eq of 2N LDA in THF (4.81 mL, 9.6 mmol, 1.4 eq) is thenadded. When the addition is complete, the reaction mixture is maintainedat −70° C. for 90 minutes. A saturated NH₄Cl solution (30 mL) as well asAcOEt (60 mL) are then added, and the reaction mixture is slowlyreturned to ambient temperature. The mixture is extracted with AcOEt(2×100 mL). The organic phases are combined, dried and then concentratedunder reduced pressure. The product obtained is, purified by flashchromatography on silica gel using as eluant an AcOEt/THF gradient(50:50 to 20:80). Intermediate 197 (0.808 g, 1.86 mmol), a mixture ofdiastereoisomers, is obtained in the form of a yellow oil with a yieldof 27%.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.25 (m, 5H), 3.55 (m, 2H), 3.25 (m,2H), 2.91 (m, 1H), 2.72 (m, 2H), 2.6/2.3 (m, 4H), 2.15/1.65 (m, 2H),1.39 (s, 9H), 1.15 (m, 12H)

³¹P NMR: (400 MHz, DMSO-d6) δ ppm 68.58

Intermediate 198: tert-Butyl (3aR*, 4S*,6aS)-2-benzyl-4-{4-[bis(tert-butoxy-carbonyl)amino]butyl}-5-[di(propan-2-yl)amino]-5-oxo-octahydrophospholo[3,4-c]pyrrole-4-carboxylate

A solution of intermediate 204 (0.71 g, 2 mmol, 1.1 eq) in DMSO (1.5 mL)is added under argon to a 60% suspension of NaH (0.12 g, 2 mmol, 1.1 eq)in DMSO (6 mL). Intermediate 197 (0.8 g, 1.84 mmol) in solution in DMSO(2 mL) is then added and the mixture is stirred for 15 hours at ambienttemperature. The reaction mixture is then hydrolysed at 0° C. with anaqueous NH₄Cl solution (10 mL) and extracted with DCM (50 mL). Theorganic phase is washed with H₂O (2×10 mL), dried over MgSO₄ andconcentrated in vacuo. The residue obtained is purified by flashchromatography on silica gel using as eluant an AcOEt/THF gradient (from100% to 80:20). Intermediate 198 (0.232 g, 0.33 mmol), a mixture ofdiastereoisomers, is obtained in the form of an oil with a yield of 18%.

¹H NMR: (400 MHz, dmso-d6) δ ppm 7.3 (m, 4H), 7.22 (m, 1H), 3.58/3.43(d)+(d, 1+1H), 3.42 (m, 2H), 3.29 (m, 1H), 3.1/2.09 (m)+(m, 1+1H), 2.87(m, 1H), 2.82/2.59 (m)+(m, 1+1H), 2.81 (m, 1H), 2.05/1.46 (m)+(m, 1+1H),1.92/1.65 (m)+(m, 1+1H), 1.45 (m, 2H), 1.42 (2*(s, 27H), 1.26/1.09(m)+(m, 1+1H), 1.17 (d, 12H)

¹³C NMR: (400 MHz, DMSO-d6) δ ppm 128.1, 126.6, 60.8, 59.1, 55.7, 45.5,45.4, 44.1, 34.3, 29.1, 27.7, 27.3, 26.6, 22.9, 22.3

Example 262:(3aR*,4S*,6aS*)-4-(4-Aminobutyl)-2-benzyl-5-hydroxy-5-oxo-octa-hydrophospholo[3,4-c]pyrrole-4-carboxylicAcid, Trifluoroacetate

Intermediate 198 (0.232 g, 0.328 mmol) and 6N hydrochloric acid (5 mL,30 mmol) are heated at reflux for 7 hours. The reaction mixture isconcentrated under reduced pressure and then lyophilised. The residue ispurified by reverse-phase chromatography on RP18 silica gel using aseluant an H₂O/MeCN/TFA gradient. Example 262 (0.040 g, 0.109 mmol) isobtained in the form of a TFA salt after lyophilisation with a yield of33%.

¹H NMR: (500 MHz, D₂O+NaOD) δ ppm 7.4-7.25 (m, 5H), 3.59 (m, 2H),3.18/2.07 (m)+(m, 1+1H), 2.9 (m, 1H), 2.84/2.37 (m)+(m, 1+1H), 2.7 (m,1H), 2.48 (m, 2H), 1.85/1.31 (m)+(m, 1+1H), 1.78/1.22 (m)+(m, 1+1H),1.31 (m, 2H), 1.24/1.07 (m)+(m, 1+1H)

¹³C NMR: (500 MHz, D2O+NaOD) δ ppm 127-129, 60.9, 59.2, 55.5, 44.1,40.1, 33.5, 32.2, 29.3, 28, 23

ESI/FIA/HR and MS/MS: [M+H]+=367.1789 (367.1786)

Preparation of Example 263

Intermediate 196 (6.15 g, 18.4 mmol) and 6N hydrochloric acid (12.2 mL,73.2 mmol) are heated at reflux for 6 hours. The reaction mixture isconcentrated in vacuo, taken up in ethanol (50 mL) and concentratedunder reduced pressure. Intermediate 199 (7.57 g, 26.3 mmol) is usedwithout being purified further.

¹H NMR: (400 MHz, dmso-d6) δ ppm 11.2 (sl, 1H), 7.6 (m, 2H), 7.4 (m,3H), 4.3 (d, 2H), 2.95;2.8 (m, 2*1H H), 3.6;3.3 (m, 2H), 3.2;2.95 (m,2H), 1.85;1.5 (m, 4H)

Intermediates 200 and 201

An oxalyl chloride solution (3.16 mL, 36.8 mmol, 2 eq) is added dropwiseto a solution of intermediate 199 (5.29 g, 18.4 mmol) in solution in DCM(170 mL) at 0° C. and under an argon atmosphere. The reaction mixture isstirred for 4 hours at ambient temperature, evaporated in vacuo and thendried under reduced pressure. The residue is taken up in anhydrous DCM(150 mL), and DMAP (0.0225 g, 0.18 mmol) is then added. The mixture iscooled to −70° C. TEA (3.1 mL, 22 mmol, 1.2 eq) and EtOH (1.3 mL, 22mmol, 1.2 eq) are added in succession. The mixture is stirred for 2hours at ambient temperature, poured onto an aqueous NH₄Cl solution andthen rendered basic with an aqueous NaHCO₃ solution. The solution isextracted with DCM (150 mL). The organic phase is washed with H₂O (2×50mL), dried over Na₂SO₄ and then concentrated in vacuo. The productobtained is purified by flash chromatography on silica gel using aDCM/EtOH gradient (from 95:5 to 85:15) as eluant. Intermediates 200(0.291 g, 1.04 mmol) and 201 (2.95 g, 10.56 mmol) are obtained with ayield of 5% and 57%, respectively.

Intermediate 202

A 2M LDA solution in THF (14.7 mmol, 7.39 mL, 1.4 eq) is added to asolution of intermediate 201 (2.95 g, 10.5 mmol) in THF (31 mL) at −70°C. and under argon. After 15 minutes at −70° C., a solution of Boc₂O(4.16 g, 14.7 mmol, 1.4 eq) in 10 mL of THF is then added dropwise.Stirring is maintained for 90 minutes, and 1.4 eq of 2M LDA in THF (14.7mmol, 7.39 mL) are then added dropwise. When the addition is complete,the reaction mixture is maintained at −70° C. for 90 minutes. Asaturated NH₄Cl solution (30 mL) as well as AcOEt (60 mL) are added, andthe reaction mixture is brought slowly to ambient temperature again. Theproduct is then extracted with AcOEt (2×150 mL). The organic phases arecombined, washed with a saturated NaCl solution (2×150 mL), dried overMgSO₄ and concentrated under reduced pressure. The residue obtained ispurified by flash chromatography on silica gel using an AcOEt/THEgradient (from 100% to 70:30) as eluant. Intermediate 202 (2.52 g, 6.64mmol) is obtained in the form of a yellowish oil with a yield of 63%.

Intermediate 203: tert-Butyl(3aR*,4R*,6aS*)-2-benzyl-4-{4-[bis(tert-butoxycarbonyl)-amino]butyl}-5-ethoxy-5-oxo-octahydrophospholo[3,4-c]pyrrole-4-carboxylate

DMSO (5 mL) and 60% NaH (0.425 g, 10.6 mol, 1.6 eq) are introduced insuccession, under an argon atmosphere, into a 250 mL three-necked flask.The flask is maintained at ambient temperature by means of a water bath.A solution of intermediate 204 (2.57 g, 7.3 mol, 1.1 eq) in DMSO (7.2mL) is then added dropwise over a period of 5 minutes. A solution ofintermediate 202 (2.52 g, 6.64 mmol) in DMSO (7.2 mL) is then addeddropwise, the temperature being maintained below 20° C. After 7 hours,the reaction mixture is cooled by means of an ice-water bath andhydrolysed by addition of 5 mL of a saturated NH₄Cl solution. Themixture is then extracted with DCM (3×50 mL). The organic phases arethen combined, washed with a saturated NaCl solution (2×50 mL) and driedover MgSO₄, before being concentrated under reduced pressure. Theresidue so obtained is purified by chromatography on silica gel using anAcOEt/THF mixture (from 100% to 80:20) as eluant. Intermediate 203 (1.86g, 2.86 mmol) is obtained with a yield of 43%.

¹H NMR: (500 MHz, CDCl₃) δ ppm 7.29 (m, 4H), 7.23 (m, 1H), 4.15 (m, 2H),3.66/3.58 (d)+(d, 1+1H), 3.58 (m, 2H), 3.06/2.49 (m)+(m, 1+1H),2.99/2.23 (m)+(m, 1+1H), 2.73 (m, 1H), 2.69 (m, 1H), 2.07/1.63 (m)+(m,1+1H), 2.02/1.78 (m)+(m, 1+1H), 1.65-1.5 (m, 2H), 1.45/1.19 (s)+(s,18+9H), 1.4 (m, 2H), 1.31 (t, 3H)

¹³C NMR: (500 MHz, CDCl₃) δ ppm 128.1, 126.6, 61.2, 60.4, 59.4, 56.7,45.8, 45.1, 33.8, 32.9, 29.2, 27.9, 26.9, 22.1, 16.5

³¹P NMR: (500 MHz, CDCl₃) δ ppm 74.9

Example 263:(3aR*,4R*,6aS*)-4-(4-Aminobutyl)-2-benzyl-5-hydroxy-5-oxo-octa-hydrophospholo[3,4-c]pyrrole-4-carboxylicAcid

Intermediate 203 (1.85 g, 2.84 mmol) and trimethylsilane bromide (4.5mL, 34.11 mmol, 12 eq) in solution in DCM (20 mL) are stirred overnightat ambient temperature and then concentrated in vacuo. The residue istaken up in MeOH (20 mL), stirred for 20 minutes and then concentratedin vacuo. The product is taken up in DCM (20 mL), and TFA (4.22 mL, 56.8mmol, 20 eq) is added. The mixture is stirred overnight at ambienttemperature. The reaction mixture is then concentrated under reducedpressure and purified by reverse-phase chromatography using an H₂O/CH₃CNgradient as eluant. Example 263 (0.29 g, 0.79 mmol) is obtained in theform of a lyophilisate with a yield of 28%.

¹H NMR: (500 MHz, D₂O+NaOD) δ ppm 7.4-7.25 (m, 5H), 3.57 (m, 2H),3.08/2.38 (m, 1+1H), 3.04/2.17 (m)+(m, 1+1H), 2.52 (t, 2H), 2.45 (m,1H), 2.42 (m, 1H), 1.73/1.45 (m)+(m, 1+1H), 1.67 (m, 2H), 1.35 (m, 2H),1.28 (m, 2H)

¹³C NMR: (500 MHz, D₂O+NaOD) δ ppm 127-129, 60.5, 59.1, 57.4, 46.1, 40,33.9, 33.2, 32.4, 28.3, 22.9

C=58.27 (59.01); H=7.24 (7.43); N=7.58 (7.65)

ESI/FIA/HR and MS/MS: [M+H]+=367.1775 (367.1786)

Pharmacological Study Example 264: Inhibition of TAFIa (hippuryl-ArgTest)

Human TAFI (4 nM) is incubated with human thrombin (10 nM) and humanthrombomodulin (5 nM) in the presence of calcium (10 mM). Afterincubation for 20 minutes, the activation reaction is stopped byaddition of PPACK (1 μM final), an irreversible thrombin inhibitor. Thereactions take place in Hepes buffer (25 mM Hepes, 137 mM NaCl, 3.5 mMKCl)+0.1% bovine albumin, pH 7.4 at 28° C. and with stirring.

The test compound is added to the solution of TAFIa (2 nM) and incubatedfor 45 minutes in the presence of hippuryl-arginine (5 mM). The reactionis stopped by addition of hydrochloric acid (1M) neutralisedsubsequently with sodium hydroxide (1M), and then the mixture isbuffered with disodium hydroxyphosphate (1M pH 7.4). The reactionproduct—hippuric acid—is revealed by addition of cyanuryl chloride (6%).The reaction mixture is stirred (vortex) and then centrifuged. Thesupernatant is transferred to a 96-well microplate, and the absorbanceis measured using a spectrophotometer at 405 nm (Spectramax plus,Molecular Devices).

The OD value of a well containing the reagents without TAFI issubtracted from all the OD values measured. The percentage inhibition ofTAFIa at a given concentration of the test compound is determined bymeans of the following formula:% inhibition=100−[(OD compound×100)/OD carrier]

The compounds are evaluated at 10 nM and 20 nM under the experimentalconditions described above and the results are expressed as thepercentage inhibition relative to a control containing the carrier inthe absence, of compound.

% inhibition % inhibition Example at 10 nM at 20 nM  48 45 (+/−6) 54(+/−9)  49 60 (+/−3) 73 (+/−3)  50 53 (+/−5) 66 (+/−6) 104 37 (+/−13) 68(+/−3) 105 44 (+/−10) 66 (+/−10) 108 25 (+/−1) 29 (+/−6) 109 58 (+/−10)71 (+/−9) 113 68 (+/−14) 90 (+/−9) 114 42 (+/−11) 51 (+/−1) 164 66(+/−18) 87 (+/−10) 165 76 (+/−8) 91 (+/−4) 166 66 (+/−11) 93 (+/−14) 16761 (+/−3) 67 (+/−1) 174 43 (+/−12) 51 (+/−2) 175 55 (+/−2) 77 (+/−1) 17974 83 (+/−3) 180 54 (+/−8) 73 (+/−9) 182 81 (+/−1) 95 (+/−7) 183 73(+/−8) 88 (+/−14) 184 67 (+/−6) 95 (+/−1) 185 69 (+/−1) 85 (+/−0) 187 74(+/−14) 97 (+/−2) 188 64 (+/−1) 86 (+/−14) 189 71 (+/−8) 78 (+/−7) 19088 (+/−12) 95 (+/−6) 191 66 (+/−4) 83 (+/−4) 192 77 (+/−11) 91 (+/−6)194 64 (+/−2) 80 (+/−0) 195 74 (+/−4) 87 (+/−3) 196 77 (+/−1) 91 (+/−1)197 60 (+/−1) 78 (+/−1) 198 72 (+/−6) 91 (+/−5) 199 54 (+/−6) 73 (+/−2)200 28 (+/−11) 46 (+/−8) 201 69 (+/−5) 84 (+/−3) 202 74 (+/−3) 87 (+/−2)203 75 (+/−4) 89 (+/−1) 204 70 (+/−7) 86 (+/−2) 206 67 (+/−7) 80 (+/−5)207 71 (+/−13) 85 (+/−10) 208 35 (+/−2) 46 (+/−7) 209 76 (+/−4) 87(+/−2) 210 71 79 (+/−9) 211 85 (+/−2) 95 (+/−0) 212 62 (+/−6) 86 (+/−2)213 83 (+/−4) 92 (+/−1) 214 79 (+/−4) 91 (+/−1) 215 82 (+/−4) 91 (+/−2)216 71 (+/−4) 85 (+/−4) 217 66 (+/−10) 83 (+/−5) 218 67 (+/−6) 83 (+/−6)219 92 (+/−9) 98 (+/−3) 220 83 (+/−3) 97 (+/−1) 221 75 (+/−2) 88 (+/−3)222 73 (+/−5) 85 (+/−4) 223 71 (+/−2) 83 (+/−4) 224 86 (+/−3) 93 (+/−2)225 76 (+/−2) 85 (+/−3) 226 71 (+/−3) 88 (+/−3) 227 84 (+/−7) 91 (+/−13)228 63 (+/−4) 82 (+/−1) 229 81 89 232 80 (+/−10) 89 (+/−19) 234 68(+/−8) 79 (+/−1) 235 60 (+/−3) 77 (+/−5) 236 81 (+/−4) 91 (+/−6) 237 77(+/−5) 84 (+/−4) 238 70 (+/−7) 87 (+/−0) 239 85 (+/−3) 96 (+/−4) 240 66(+/−1) 80 (+/−5) 241 77 (+/−11) 91 (+/−9) 242 75 (+/−2) 88 (+/−1) 244 49(+/−1) 68 (+/−6) 245 38 (+/−2) 52 (+/−5) 246 72 (+/−4) 86 (+/−1) 247 85(+/−16) 89 (+/−11) 248 87 (+/−14) 95 (+/−6) 249 88 (+/−6) 94 (+/−4) 25088 (+/−1) 97 (+/−1) 251 70 (+/−14) 90 (+/−11) 252 76 (+/−7) 90 (+/−2)

Example 265: Pharmaceutical Composition—Tablet

Formulation for the preparation of 1000 tablets each containing 10 mg:

Compound of one of Examples 1 to 263  10 g Hydroxypropylcellulose  2 gWheat starch  10 g Lactose 100 g Magnesium stearate  3 g Talc  3 g

Example 266: Pharmaceutical Composition—Tablet in Association withWarfarin

Formulation for the preparation of 1000 tablets each containing 10 mg:

Compound of one of Examples 1 to 263  10 g Warfarin  2 gHydroxypropylcellulose  2 g Wheat starch  10 g Lactose 100 g Magnesiumstearate  3 g Talc  3 g

Example 267: Pharmaceutical Composition—Tablet in Association withAspirin

Formulation for the preparation of 1000 tablets each containing 10 mg:

Compound of one of Examples 1 to 263  10 g Aspirin 100 gHydroxypropylcellulose  2 g Wheat starch  10 g Lactose 100 g Magnesiumstearate  3 g Talc  3 g

Example 268: Injectable Solution

Formulation for the preparation of 10 ml of solution:

Compound of one of Examples 1 to 263 200 mg Injectable preparation of0.9% NaCl  10 ml

The invention claimed is:
 1. A method of treating or preventingAlzheimer's disease in a subject in need thereof, comprisingadministration of an effective amount of a compound of formula (I):

wherein: Ak₁ represents a C₁-C₆-alkyl chain; X represents —(CH₂)_(m)—,—CH(R)—, —N(R)—, —CH₂—N(R)—, —N(R)—CH₂— or —CH₂—N(R)—CH₂—; m represents0 or an integer from 1 to 4; R represents a hydrogen atom, C₁-C₆-alkyl,-Ak₂-Ar₁, -Ak₂-Ar₁-Ar₂, -Ak₂-Ar₁—O—Ar₂, -Ak₂-cycloalkyl or -Ak₂-OH; Ak₂represents a linear or branched C₁-C₆-alkyl chain; Ar₁ and Ar₂, whichmay be identical or different, each represent an aryl or heteroarylgroup; R₁ and R₂ each represent a hydrogen atom when X represents—(CH₂)_(m)—, —CH(R)—, —N(R)—, —CH₂—N(R)— or —N(R)—CH₂—, or together forma bond when X represents —CH₂—N(R)—CH₂—; R₃ represents NH₂, Cy-NH₂,Cy-Ak₃-NH₂ or piperidin-4-yl; Cy represents cycloalkyl, aryl orheteroaryl; Ak₃ represents a C₁-C₃-alkyl chain; R₄ and R₅, which may beidentical or different, each represent a hydrogen atom or a fluorineatom; its optical isomers, or addition salts thereof with apharmaceutically acceptable acid, wherein the compound of formula (I) isadministered alone or in combination with one or more inert, non-toxic,pharmaceutically acceptable excipients or carriers.
 2. The methodaccording to claim 1, wherein R₁, R₂, R₄ and R₅ each represent ahydrogen atom; R₃ represents NH₂; X represents —N(R)—, —CH₂—N(R)—,—N(R)—CH₂— or —CH₂—N(R)—CH₂—; and R represents a group selected from-Ak₂-Ar₁, -Ak₂-Ar₁-Ar₂ and -Ak₂-Ar₁—O—Ar₂.
 3. The method according toclaim 1, wherein the compound of formula (I) is a compound of formula(Ia):

wherein Ra represents-CH₂—Ar₁ or —CH₂—Ar₁-Ar₂, wherein Ar₁ and Ar₂,which may be identical or different, each represent an aryl orheteroaryl group.
 4. The method according to claim 1, wherein thecompound of formula (I) is selected from the group consisting of(3S)-3-(4-aminobutyl)-1-[[2-(3,4-dimethoxyphenyl)-4-fluorophenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 5. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-1-[[4-fluoro-2-(4-methylphenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 6. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-1-[[4-fluoro-2-(4-methoxyphenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 7. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-1-[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 8. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-4-hydroxy-1-[(4-hydroxy-2-phenylphenyl)methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 9. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-4-hydroxy-1-[2-(6-methoxypyridin-3-yl)benzyl]-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 10. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-1-[[2-(4-chlorophenyl)-4-fluorophenyl]methyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 11. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-1-[4-fluoro-2-(1-methyl-1H-imidazol-5-yl)benzyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 12. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-1-[2-(1,2-dimethyl-1H-imidazol-5-yl)-4-fluorobenzyl]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 13. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-4-hydroxy-1-[[4-hydroxy-2-(4-methylphenyl)phenyl]methyl]-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 14. The method according to claim 1,wherein the compound of formula (I) is selected from the groupconsisting of(3S)-3-(4-aminobutyl)-4-hydroxy-1-[4-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)benzyl]-4-oxo-1,4-azaphosphinane-3-carboxylicacid, and its optical isomers, and addition salts thereof with apharmaceutically acceptable acid.
 15. The method according to claim 1,wherein the compound of formula (I) is administered in combination witha fibrinolytic, an anticoagulant or an anti-platelet agent.
 16. Themethod according to claim 15, wherein the fibrinolytic is an injectablefibrinolytic selected from the group consisting of alteplase andtenecteplase.